ORCID Profile
0000-0003-3670-9399
Current Organisation
University of South Australia
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Animal Breeding | Genomics | Genetics | Quantitative Genetics (incl. Disease and Trait Mapping Genetics)
Expanding Knowledge in the Agricultural and Veterinary Sciences | Expanding Knowledge in the Biological Sciences | Application Software Packages (excl. Computer Games) |
Publisher: Frontiers Media SA
Date: 27-05-2022
Abstract: This systematic review and meta-analysis of prospective cohort studies examined the associations between egg and dietary cholesterol intake and the risk of mortality from all causes, including cardiovascular disease (CVD) and cancer. We searched PubMed, Scopus, ISI Web of Knowledge, and Google Scholar until April 2021, as well as references to the relevant articles retrieved. Random-effects models were used to calculate summary relative risk (RR) and 95% confidence intervals (CIs) for the highest vs. lowest categories of egg and dietary cholesterol intake. Also, linear and non-linear dose–response analyses were conducted to examine the dose-response relationships. We included 55 studies, comprising data from 2,772,486 in iduals with 228,425, 71,745, and 67,211 cases of all-cause, CVD, and cancer mortality, respectively. Intake of each additional egg per day was associated with a 7% higher risk of all-cause (1.07, 95% CI: 1.02–1.12, I 2 = 84.8%) and a 13% higher risk of cancer mortality (1.13, 95% CI: 1.06–1.20, I 2 = 54.2%), but was not associated with CVD mortality (1.00, 95% CI: 0.92–1.09, I 2 = 81.5%). Non-linear analyses showed increased risks for egg consumption of more than 1.5 and 0.5 eggs/day, respectively. Each 100 mg/day increment in dietary cholesterol intake was associated with a 6% higher risk of all-cause mortality (1.06, 95% CI: 1.03–1.08, I 2 = 34.5%) and a 6% higher risk of cancer mortality (1.06, 95% CI: 1.05–1.07, I 2 = 0%), but was not associated with CVD mortality (1.04, 95% CI: 0.99–1.10, I 2 = 85.9%). Non-linear analyses demonstrated elevated risks of CVD and cancer mortality for intakes more than 450 and 250 mg/day, respectively. High-dietary intake of eggs and cholesterol was associated with all-cause and cancer mortality. Little evidence for elevated risks was seen for intakes below 0.5 egg/day or 250 mg/day of dietary cholesterol. Our findings should be considered with caution because of small risk estimates and moderate between-study heterogeneity. www.crd.york.ac.uk rospero/display_record.php?RecordID=252564 , PROSPERO, identifier: CRD42021252564.
Publisher: Oxford University Press (OUP)
Date: 09-2004
Publisher: Springer Science and Business Media LLC
Date: 11-12-2012
DOI: 10.1007/S00198-012-2231-3
Abstract: On September 29, 2011, acknowledged experts in the field of vitamin D, mainly European, were brought together in order to discuss the recent scientific advances in relation to vitamin D: the current requirements and associations with various health outcomes. In this article, the discussions resulting from the meeting are summarized. Several groups at risk for developing vitamin D insufficiency have been identified. Accordingly, reviews indicate that a significant percentage of the population worldwide have serum 25-hydroxyvitamin D levels below 50 nmol/l. In addition to the role of vitamin D in bone health, recent studies suggest that it may play a pivotal role in other systems, e.g., the cardiovascular system, pancreas, muscle, immune system and brain. Most evidence, however, is obtained from observational studies and yet inconclusive. To exchange and broaden knowledge on the requirements for vitamin D and its effect on various health outcomes, a workshop entitled "Vitamin D Expert Meeting: Do we get enough?", was organized. Despite low vitamin D levels worldwide, consensus on the definition of deficiency is not yet reached. In order to define cut-off points for vitamin D whilst taking into account extraskeletal health effects, randomized controlled trials in these fields are warranted. The experts do emphasize that there is evidence to suggest an important role for vitamin D in the maintenance of optimal bone health at all ages and that vitamin D supplementation, in most studies co-administered with calcium, reduces fracture risk in the senior population. To reach a serum 25-hydroxyvitamin D level of 50 nmol/l older adults aged ≥65 years are therefore recommended to meet a mean daily vitamin D intake of 20 μg (800 IU), which is best achieved with a supplement.
Publisher: Oxford University Press (OUP)
Date: 27-01-2017
Abstract: Pregnancy and infancy comprise the most critical stages for conditioning an in idual's health, with a number of implications for subsequent risks of morbidity, mortality, and reproductive health. Nutrition may influence both the overall pregnancy outcome and the growth trajectory and immune system of the fetus and infant, with short- and long-term effects on the health of the offspring. Within this context, leading experts at Expo Milano 2015 in Milan, Italy, discussed up-to-date knowledge while providing suggestions and challenges before, during, and after pregnancy. This narrative review summarizes the key issues raised by the experts concerning the interplay between the nutritional environment from conception to early infancy and the offspring's immediate and lifelong health, with a particular focus on epigenetic mechanisms, probiotics, vitamin D, and breastfeeding. Taken together, the findings strengthen the awareness that nutritional exposures occurring from preconception to the postnatal period may be strong determinants of the offspring's health and may provide supportive evidence for current nutritional recommendations and guidelines for pregnant women and infants. Critical topics to be addressed in future research and translated into recommendations of public health relevance are also highlighted.
Publisher: Elsevier BV
Date: 06-2020
Publisher: MDPI AG
Date: 29-05-2023
DOI: 10.3390/NU15112522
Abstract: Background: Infertility and fecundability problems have been linked with lower 25-hydroxyvitamin D (25(OH)D) concentrations, but studies conducted with small, heterogenous or selected populations have shown inconsistent results. Methods: This study included women at age 31 from prospective population-based Northern Finland Birth Cohort 1966. Serum 25(OH)D concentrations were evaluated between women with or without previous infertility examinations or treatments (infertility group, n = 375, reference group, n = 2051) and time to pregnancy (TTP) of over 12 months (decreased fecundability group, n = 338) with a wide range of confounders. Furthermore, 25(OH)D concentrations were also compared among reproductive outcomes. Results: The mean 25(OH)D concentration was lower and 25(OH)D 30 nmol/L was more frequent in women with a history of infertility compared to reference group. Moreover, 25(OH)D 75 nmol/L was more frequent in the reference group. The mean 25(OH)D concentration was lower in women who had had multiple miscarriages. Both history of infertility (β = −2.7, 95% confidence interval (CI) −4.6, −0.7) and decreased fecundability associated with lower 25(OH)D concentration (β = −4.1, 95% CI −7.4, −0.8) after adjustments. In conclusion, this population-based study demonstrated that previous infertility and decreased fecundability were associated with lower 25(OH)D.
Publisher: Wiley
Date: 06-09-2016
DOI: 10.1002/JCLA.22049
Publisher: Cambridge University Press (CUP)
Date: 02-07-2010
DOI: 10.1017/S0007114510002436
Abstract: Prevalence of hypovitaminosis D in Western populations is high pregnant women are identified as a high-risk group, especially if dark skinned. Consequences of severe clinical vitamin D deficiency in pregnancy can be life threatening to the newborn, while lesser degrees of hypovitaminosis D may have important long-term implications for offspring health. Past experiences with routine provision of 10 μg/d (400 IU/d) to all pregnant mothers suggest that this dose is sufficient to prevent overt neonatal complications of vitamin D deficiency. Recent data suggest that supplementation with dosages above 10 μg/d may be required for optimal health in the mother and child however, further research is required for the assessment of the benefits and safety of supplementation with higher dosages. Lack of unified advice on vitamin D supplementation of pregnant mothers in the UK hinders the implementation of primary prevention strategies and is likely to leave some deficient mothers without supplementation.
Publisher: S. Karger AG
Date: 2013
DOI: 10.1159/000358338
Abstract: b i Background/Aims: /i /b Vitamin D may protect from pre-ecl sia through influences on immune modulation and vascular function. To evaluate the role of vitamin D in the development of pre-ecl sia, we conducted a systematic review and meta-analysis including novel data from 2 large-scale epidemiological studies. b i Methods: /i /b PubMed, EMBASE and the Cochrane Central Register of Controlled Trials were searched for prospective observational studies of association between vitamin D supplementation or status (measured by maternal 25-hydroxyvitamin D, 25(OH)D) with a subsequent risk of pre-ecl sia, or randomised controlled trials using vitamin D supplementation to prevent pre-ecl sia. The Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA) and the Avon Longitudinal Study of Parents and Children (ALSPAC) were included in meta-analyses with published studies. b i Results: /i /b Mothers receiving vitamin D supplementation earlier in pregnancy had lower odds of pre-ecl sia [pooled odds ratios (OR) 0.81 and 95% confidence interval (CI) 0.75-0.87, p = 2.4 × 10 sup -8 /sup , 2 studies] in the meta-analysis of published studies with HCCSCA. The meta-analysis of published studies with ALSPAC suggested an association between higher serum 25(OH)D levels and a reduced risk of pre-ecl sia (pooled OR 0.52 and 95% CI 0.30-0.89, p = 0.02, 6 studies). Randomised trials of supplementation were suggestive of protective association (pooled OR 0.66 and 95% CI 0.52-0.83, p = 0.001, 4 studies). b i Conclusions: /i /b This study suggests that low maternal serum 25(OH)D concentrations increase pre-ecl sia risk and that vitamin D supplementation lowers this risk. The quality of evidence is insufficient to determine a causal association, which highlights the need for adequately powered clinical trials.
Publisher: Springer Science and Business Media LLC
Date: 06-07-2012
Abstract: A season of birth effect in immune-mediated diseases (ID) such as multiple sclerosis and type 1 diabetes has been consistently reported. We aimed to investigate whether season of birth influences the risk of rheumatoid arthritis, Crohn's disease, ulcerative colitis and systemic lupus erythematosus in addition to multiple sclerosis, and to explore the correlation between the risk of ID and predicted ultraviolet B (UVB) light exposure and vitamin D status during gestation. The monthly distribution of births of patients with ID from the UK (n = 115,172) was compared to that of the general population using the Cosinor test. Predicted UVB radiation and vitamin D status in different time windows during pregnancy were calculated for each month of birth and correlated with risk of ID using the Spearman's correlation coefficient. The distributions of ID births significantly differed from that of the general population ( P = 5e -12 ) with a peak in April (odds ratio = 1.045, 95% confidence interval = 1.024, 1.067, P 0.0001) and a trough in October (odds ratio = 0.945, 95% confidence interval = 0.925, 0.966, P 0.0001). Stratification by disease subtype showed seasonality in all ID but Crohn's disease. The risk of ID was inversely correlated with predicted second trimester UVB exposure (Spearman's rho = -0.49, P = 0.00005) and third trimester vitamin D status (Spearman's rho = -0.44, P = 0.0003). The risk of different ID in the UK is significantly influenced by the season of birth, suggesting the presence of a shared seasonal risk factor or factors predisposing to ID. Gestational UVB and vitamin D exposure may be implicated in the aetiology of ID.
Publisher: BMJ
Date: 08-2015
Publisher: American Diabetes Association
Date: 09-2003
DOI: 10.2337/DIACARE.26.9.2512
Abstract: OBJECTIVE—Small size at birth has been associated with increased risk of type 2 diabetes. Our aim was to evaluate how risk of diabetes associated with low birth weight is affected by accumulation of body mass from childhood to adulthood. RESEARCH DESIGN AND METHODS—Subjects from the 1958 British birth cohort (born 3–9 March 1958) have been followed regularly since birth. In the survey at 41 years of age, 88 participants reported type 2 diabetes (n = 10,683). RESULTS—Participants in whom diabetes developed weighed less at birth and had higher BMIs than the others. Birth weight (adjusted for gestational age and sex) was inversely related to risk of diabetes (odds ratio for 1-SD change 0.76, 95% CI 0.56–0.99). All diabetic participants in the lowest third of birth weight were in the highest third of weight gain by 23 years of age. An increased risk of diabetes was found for those in the lowest third of BMI at 7 years of age (2.84, 1.2–6.9), but diabetic participants in this group had excessive weight gain to 23 years of age. All but one diabetic participant in the highest third of childhood BMI remained in the highest third until 23 years of age. Risk of diabetes by BMI at 23 years of age was 22.9-fold (95% CI 12–42) for obese participants and 3.8-fold (2.1–6.9) for overweight participants compared with those of normal weight. CONCLUSIONS—There was no increase in risk of diabetes for small size at birth without excessive postnatal weight gain. Adult obesity was the most important risk factor for type 2 diabetes developing by early midlife.
Publisher: Oxford University Press (OUP)
Date: 04-11-2022
DOI: 10.1093/PM/PNAC170
Abstract: Depression frequently coexists with chronic pain. Contemporary models suggest that these conditions share pathobiological mechanisms, prompting a need to investigate their temporal association. This investigation aimed to explore two distinctly different chronic pain conditions, and their cross-sectional and prospective associations with depression. Self-reported information was available on chronic widespread pain (CWP), chronic low back pain (CLBP) (45 years), and depression symptoms (45 and 50 years) from up to 9,377 participants in the 1958 British cohort. Depression symptom outcomes were derived by “Clinical Interview Schedule-Revised” (45 years) and “Short Form-36” (50 years). Relationships between both chronic pain conditions and depression symptoms were investigated by fitting four separate logistic regression models, each with varying levels of covariate adjustment, including depression at baseline. CWP was associated with depression symptoms cross-sectionally (odds ratio [OR] = 2.04, 95% confidence interval [CI] 1.65, 2.52 P & 0.001, n = 7,629), and prospectively when fully adjusted for baseline, sociodemographic, lifestyle, and health covariates (OR = 1.45, 95% CI 1.17, 1.80 P = & 0.001, n = 6,275). CLBP was associated with depression symptoms prospectively (full model: OR = 1.28, 95% CI 1.01, 1.61 P = 0.04, n = 6,288). In fully adjusted models the prospective association of CWP with depression symptoms was more heavily influenced by our covariates than CLBP with depression symptoms. Pain may be a stressor from which depression can arise. Development of depression may be differentially dependant upon the type of pain experienced. Screening for depression symptoms among in iduals with both chronic pain conditions is indicated and should be repeated over time.
Publisher: Springer Science and Business Media LLC
Date: 17-09-2018
Publisher: Elsevier BV
Date: 04-2002
Publisher: BMJ
Date: 04-01-2003
Publisher: Oxford University Press (OUP)
Date: 28-01-2014
Publisher: Springer Science and Business Media LLC
Date: 28-09-2016
DOI: 10.1038/NATURE19806
Publisher: American Medical Association (AMA)
Date: 27-03-2006
DOI: 10.1001/ARCHINTE.166.6.682
Abstract: The Cambridge Risk Score (CRS) was developed to screen for type 2 diabetes mellitus risk. We assessed the ability of the CRS to predict glycosylated hemoglobin (HbA(1c)) levels and determined whether the CRS was better than body mass index (BMI) at predicting HbA(1c) levels in midlife. We included 7452 participants without known diabetes in a biomedical survey of the 1958 British Birth Cohort at 45 years of age. Receiver operator characteristic curves were used to compare the ability of the CRS and BMI to identify in iduals with elevated HbA(1c) levels using thresholds of 7.0% or more, 6.0% or more, and 5.5% or more. Of the total s le, 0.9% (95% confidence interval [CI], 0.7%-1.1%) had HbA(1c) levels of 7.0% or more 3.8% (95% CI, 3.2%-4.5%), 6.0% or more and 24.4% (95% CI, 23.1%-25.9%), 5.5% or more. The CRS detected in iduals with elevated HbA(1c) levels with reasonable accuracy (area under the curve, 0.84 for HbA(1c) level >or=7.0% 0.76 for HbA(1c) level >or=6.0%). Similar area under the curve values were obtained using BMI alone (0.84 for HbA(1c) level >or=7.0% 0.79 for HbA(1c) level >or=6.0%). When tested using the lower HbA(1c) threshold of 5.5% or more, the CRS and BMI did not perform well (areas under the curve, 0.65 and 0.63 for CRS and BMI, respectively). Both measures indicated that approximately 20% of the cohort were at increased risk of diabetes. Owing to the low prevalence of diabetes at 45 years of age, only 2% to 3% of those considered at risk had elevated HbA(1c) levels. For a population in mid-adult life, the CRS identified in iduals with elevated HbA(1c) levels reasonably well. However, the CRS had no advantage compared with BMI alone in identifying diabetes risk.
Publisher: Cambridge University Press (CUP)
Date: 2015
Publisher: Springer Science and Business Media LLC
Date: 02-03-2023
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.JAAC.2021.11.035
Abstract: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for s le overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. The meta-analysis of overall internalizing symptoms (INT Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood s les will be key in paving the way to future GWAS success.
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.METABOL.2022.155342
Abstract: Analyses to predict the risk of cancer typically focus on single biomarkers, which do not capture their complex interrelations. We hypothesized that the use of metabolic profiles may provide new insights into cancer prediction. We used information from 290,888 UK Biobank participants aged 37 to 73 years at baseline. Metabolic subgroups were defined based on clustering of biochemical data using an artificial neural network approach and examined for their association with incident cancers identified through linkage to cancer registry. In addition, we evaluated associations between 38 in idual biomarkers and cancer risk. In total, 21,973 in iduals developed cancer during the follow-up (median 3.87 years, interquartile range [IQR] = 2.03-5.58). Compared to the metabolically favorable subgroup (IV), subgroup III (defined as "high BMI, C-reactive protein & cystatin C") was associated with a higher risk of obesity-related cancers (hazard ratio [HR] = 1.26, 95 % CI = 1.21 to 1.32) and hematologic-malignancies (e.g., lymphoid leukemia: HR = 1.83, 95%CI = 1.44 to 2.33). Subgroup II ("high triglycerides & liver enzymes") was strongly associated with liver cancer risk (HR = 5.70, 95%CI = 3.57 to 9.11). Analysis of in idual biomarkers showed a positive association between testosterone and greater risks of hormone-sensitive cancers (HR per SD higher = 1.32, 95%CI = 1.23 to 1.44), and liver cancer (HR = 2.49, 95%CI =1.47 to 4.24). Many liver tests were in idually associated with a greater risk of liver cancer with the strongest association observed for gamma-glutamyl transferase (HR = 2.40, 95%CI = 2.19 to 2.65). Metabolic profile in middle-to-older age can predict cancer incidence, in particular risk of obesity-related cancer, hematologic malignancies, and liver cancer. Elevated values from liver tests are strong predictors for later risk of liver cancer.
Publisher: BMJ
Date: 14-10-2013
Publisher: Wiley
Date: 30-10-2018
DOI: 10.1111/ADD.14438
Abstract: To use the rs1229984 variant associated with alcohol consumption as an instrument for alcohol consumption to test the causality of the association of alcohol consumption with hay fever, asthma, allergic sensitization and serum total immunoglobulin (Ig)E. Observational and Mendelian randomization analyses using genetic variants as unbiased markers of exposure to estimate causal effects, subject to certain assumptions. Europe. We included a total of 466 434 people aged 15-82 years from 17 population-based studies conducted from 1997 to 2015. The rs1229984 (ADH1B) was genotyped alcohol consumption, hay fever and asthma were self-reported. Specific and total IgE were measured from serum s les. Observational analyses showed that ever-drinking versus non-drinking, but not amount of alcohol intake, was positively associated with hay fever and inversely associated with asthma but not with allergic sensitization or serum total immunoglobulin (Ig)E. However, Mendelian randomization analyses did not suggest that the observational associations are causal. The causal odds ratio (OR) per genetically assessed unit of alcohol/week was an OR = 0.907 [95% confidence interval (CI) = 0.806, 1.019 P = 0.101] for hay fever, an OR = 0.897 (95% CI = 0.790, 1.019 P = 0.095) for asthma, an OR = 0.971 (95% CI = 0.804, 1.174 P = 0.763) for allergic sensitization and a 4.7% change (95% CI = -5.5%, 14.9% P = 0.366) for total IgE. In observational analyses, ever-drinking versus not drinking was positively associated with hay fever and negatively associated with asthma. However, the Mendelian randomization results were not consistent with these associations being causal.
Publisher: The Endocrine Society
Date: 02-2016
DOI: 10.1210/JC.2015-2175
Publisher: Elsevier BV
Date: 08-2013
Publisher: Oxford University Press (OUP)
Date: 09-2004
DOI: 10.1301/NR.2004.SEPT.340-347
Abstract: Evidence from animal experiments and human observational studies suggests that some dietary micronutrients may protect against the development of type 1 diabetes. The most promising data so far have been obtained for a beneficial role of vitamin D. Beneficial effects of vitamin E (or other antioxidants) in diabetes development remain hypothetical. Despite plausible theoretical background evidence from animal experiments and supportive data from pilot studies, randomized, controlled trials using nicotinamide have not provided any evidence for a beneficial effect.
Publisher: Cambridge University Press (CUP)
Date: 07-12-2010
DOI: 10.1017/S0007114510002576
Abstract: The Rank Forum on Vitamin D was held on 2nd and 3rd July 2009 at the University of Surrey, Guildford, UK. The workshop consisted of a series of scene-setting presentations to address the current issues and challenges concerning vitamin D and health, and included an open discussion focusing on the identification of the concentrations of serum 25-hydroxyvitamin D (25(OH)D) (a marker of vitamin D status) that may be regarded as optimal, and the implications this process may have in the setting of future dietary reference values for vitamin D in the UK. The Forum was in agreement with the fact that it is desirable for all of the population to have a serum 25(OH)D concentration above 25 nmol/l, but it discussed some uncertainty about the strength of evidence for the need to aim for substantially higher concentrations (25(OH)D concentrations nmol/l). Any discussion of ‘optimal’ concentration of serum 25(OH)D needs to define ‘optimal’ with care since it is important to consider the normal distribution of requirements and the vitamin D needs for a wide range of outcomes. Current UK reference values concentrate on the requirements of particular subgroups of the population this differs from the approaches used in other European countries where a wider range of age groups tend to be covered. With the re-emergence of rickets and the public health burden of low vitamin D status being already apparent, there is a need for urgent action from policy makers and risk managers. The Forum highlighted concerns regarding the failure of implementation of existing strategies in the UK for achieving current vitamin D recommendations.
Publisher: Frontiers Media SA
Date: 09-03-2022
DOI: 10.3389/FGENE.2022.759309
Abstract: Metabolic syndrome is a group of heritable metabolic traits that are highly associated with type 2 diabetes (T2DM). Classical interventions to T2DM include in idual self-management of environmental risk factors, such as improving diet quality, increasing physical activity, and reducing smoking and alcohol consumption, which decreases the risk of developing metabolic syndrome. However, it is poorly understood how the phenotypes of diabetes-related metabolic traits change with respect to lifestyle modifications at the in idual level. In the analysis, we used 12 diabetes-related metabolic traits and eight lifestyle covariates from the UK Biobank comprising 288,837 white British participants genotyped for 1,133,273 genome-wide single nucleotide polymorphisms. We found 16 GxE interactions. Modulation of genetic effects by physical activity was seen for four traits (glucose, HbA1c, C-reactive protein, systolic blood pressure) and by alcohol and smoking for three (BMI, glucose, waist–hip ratio and BMI and diastolic and systolic blood pressure, respectively). We also found a number of significant phenotypic modulations by the lifestyle covariates, which were not attributed to the genetic effects in the model. Overall, modulation in the metabolic risk in response to the level of lifestyle covariates was clearly observed, and its direction and magnitude were varied depending on in idual differences. We also showed that the metabolic risk inferred by our model was notably higher in T2DM prospective cases than controls. Our findings highlight the importance of in idual genetic differences in the prevention and management of diabetes and suggest that the one-size-fits-all approach may not benefit all.
Publisher: Cold Spring Harbor Laboratory
Date: 23-11-2020
DOI: 10.1101/2020.11.22.20236505
Abstract: Metabolic syndrome is a group of heritable metabolic traits that are highly associated with type 2 diabetes (T2DM). Classical interventions to T2DM include in idual self-management of environmental risk factors such as improving diet quality, increasing physical activity and reducing smoking and alcohol consumptions, which decreases the risk of developing metabolic syndrome. However, it is poorly understood how the phenotypes of diabetes-related metabolic traits change with respect to lifestyle modifications at the in idual level. In this study, we applied a whole-genome genotype-by-environment (GxE) interaction approach to describe how intermediate traits reflecting metabolic risk are affected by genetic variations and how this genetic risk can interact with lifestyle, which can vary, conditional on in idual genetic differences. In the analysis, we used 12 diabetes-related metabolic traits and eight lifestyle covariates from the UK Biobank comprising 288,837 white British participants genotyped for 1,133,273 genome-wide single nucleotide polymorphisms. We found 17 GxE interactions, of which four modulated BMI and the others distributed across other traits. Modulation of genetic effects by physical activity was seen for four traits (glucose, HbA1c, C-reactive protein, systolic blood pressure), and by alcohol and smoking for three (BMI, glucose, waist-hip ratio and BMI, diastolic and systolic blood pressure, respectively). We also found a number of significant phenotypic modulations by the lifestyle covariates, which were not attributed to the genetic effects in the model. Overall, modulation in the metabolic risk in response to the level of lifestyle covariates was clearly observed, and its direction and magnitude were varied depending on in idual differences. We also showed that the metabolic risk inferred by our model was notably higher in T2DM prospective cases than controls. Our findings highlight the importance of in idual genetic differences in the prevention and management of diabetes and suggest that the one-size-fits-all approach may not benefit all. This study has been supported by the Australian Research Council (DP 190100766, FT 160100229).
Publisher: American Medical Association (AMA)
Date: 24-12-2008
Abstract: Low birth weight is implicated as a risk factor for type 2 diabetes. However, the strength, consistency, independence, and shape of the association have not been systematically examined. To conduct a quantitative systematic review examining published evidence on the association of birth weight and type 2 diabetes in adults. Relevant studies published by June 2008 were identified through literature searches using EMBASE (from 1980), MEDLINE (from 1950), and Web of Science (from 1980), with a combination of text words and Medical Subject Headings. Studies with either quantitative or qualitative estimates of the association between birth weight and type 2 diabetes were included. Estimates of association (odds ratio [OR] per kilogram of increase in birth weight) were obtained from authors or from published reports in models that allowed the effects of adjustment (for body mass index and socioeconomic status) and the effects of exclusion (for macrosomia and maternal diabetes) to be examined. Estimates were pooled using random-effects models, allowing for the possibility that true associations differed between populations. Of 327 reports identified, 31 were found to be relevant. Data were obtained from 30 of these reports (31 populations 6090 diabetes cases 152 084 in iduals). Inverse birth weight-type 2 diabetes associations were observed in 23 populations (9 of which were statistically significant) and positive associations were found in 8 (2 of which were statistically significant). Appreciable heterogeneity between populations (I(2) = 66% 95% confidence interval [CI], 51%-77%) was largely explained by positive associations in 2 native North American populations with high prevalences of maternal diabetes and in 1 other population of young adults. In the remaining 28 populations, the pooled OR of type 2 diabetes, adjusted for age and sex, was 0.75 (95% CI, 0.70-0.81) per kilogram. The shape of the birth weight-type 2 diabetes association was strongly graded, particularly at birth weights of 3 kg or less. Adjustment for current body mass index slightly strengthened the association (OR, 0.76 [95% CI, 0.70-0.82] before adjustment and 0.70 [95% CI, 0.65-0.76] after adjustment). Adjustment for socioeconomic status did not materially affect the association (OR, 0.77 [95% CI, 0.70-0.84] before adjustment and 0.78 [95% CI, 0.72-0.84] after adjustment). There was no strong evidence of publication or small study bias. In most populations studied, birth weight was inversely related to type 2 diabetes risk.
Publisher: Oxford University Press (OUP)
Date: 18-01-2023
DOI: 10.1093/IJE/DYAC238
Abstract: Genetic and lifestyle factors are associated with cancer risk. We investigated the benefits of adhering to lifestyle advice by the World Cancer Research Fund (WCRF) with the risk of 13 types of cancer and whether these associations differ according to genetic risk using data from the UK Biobank. In 2006–2010, participants aged 37–73 years had their lifestyle assessed and were followed up for incident cancers until 2015–2019. Analyses were restricted to those of White European ancestry with no prior history of malignant cancer (n = 195 822). Polygenic risk scores (PRSs) were computed for 13 cancer types and these cancers combined (‘overall cancer’), and a lifestyle index was calculated from WCRF recommendations. Associations with cancer incidence were estimated using Cox regression, adjusting for relevant confounders. Additive and multiplicative interactions between lifestyle index and PRSs were assessed. There were 15 240 incident cancers during the 1 926 987 person-years of follow-up (median follow-up = 10.2 years). After adjusting for confounders, the lifestyle index was associated with a lower risk of overall cancer [hazard ratio per standard deviation increase (95% CI) = 0.89 (0.87, 0.90)] and of eight specific cancer types. There was no evidence of interactions on the multiplicative scale. There was evidence of additive interactions in risks for colorectal, breast, pancreatic, lung and bladder cancers, such that the recommended lifestyle was associated with greater change in absolute risk for persons at higher genetic risk (P & 0.0003 for all). The recommended lifestyle has beneficial associations with most cancers. In terms of absolute risk, the protective association is greater for higher genetic risk groups for some cancers. These findings have important implications for persons most genetically predisposed to those cancers and for targeted strategies for cancer prevention.
Publisher: Cold Spring Harbor Laboratory
Date: 05-06-2020
DOI: 10.1101/2020.06.04.20121061
Abstract: Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium. The SNP heritability of total psychiatric problems was 5.4% (SE=0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2 , a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total psychiatric problem score were shared with known genetic variants for common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (r G 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (r G 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation of with intelligence, educational attainment, wellbeing, smoking, and body fat (r G 0.29).The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between psychiatric disorders and related traits.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-04-2020
Abstract: Both genetic and nongenetic factors can predispose in iduals to cardiovascular risk. Finding ways to alter these predispositions is important for cardiovascular disease prevention. We used a novel whole‐genome approach to estimate the genetic and nongenetic effects on—and hence their predispositions to—cardiovascular risk and determined whether they vary with respect to lifestyle factors such as physical activity, smoking, alcohol consumption, and dietary intake. We performed analyses on the ARIC (Atherosclerosis Risk in Communities) Study (N=6896–7180) and validated findings using the UKBB (UK Biobank, N=14 076–34 538). Lifestyle modulation was evident for many cardiovascular traits such as body mass index and resting heart rate. For ex le, alcohol consumption modulated both genetic and nongenetic effects on body mass index, whereas smoking modulated nongenetic effects on heart rate, pulse pressure, and white blood cell count. We also stratified in iduals according to estimated genetic and nongenetic effects that are modulated by lifestyle factors and showed distinct phenotype–lifestyle relationships across the stratified groups. Finally, we showed that neglecting lifestyle modulations of cardiovascular traits would on average reduce single nucleotide polymorphism heritability estimates of these traits by a small yet significant amount, primarily owing to the overestimation of residual variance. Lifestyle changes are relevant to cardiovascular disease prevention. In idual differences in the genetic and nongenetic effects that are modulated by lifestyle factors, as shown by the stratified group analyses, implies a need for personalized lifestyle interventions. In addition, single nucleotide polymorphism–based heritability of cardiovascular traits without accounting for lifestyle modulations could be underestimated.
Publisher: Elsevier BV
Date: 09-2014
Publisher: American Diabetes Association
Date: 04-2007
DOI: 10.2337/DC06-1881
Abstract: OBJECTIVE—Birth weight has been associated with the risk of type 2 diabetes in several studies. We investigated whether prenatal influences on birth weight (gestational age, parity, preecl sia, prepregnancy BMI, smoking during pregnancy, and socioeconomic position [SEP]) were associated with glucose metabolism in midlife and the role of birth weight for gestational age (BGA) and adult adiposity in mediating these associations. RESEARCH DESIGN AND METHODS—Data from 7,518 participants of the 1958 British Birth Cohort with information on A1C at age 45 years were analyzed. Associations between prenatal exposures and A1C ≥6% were examined using a series of logistic regression models. The basic model consisted of all prenatal factors (except parity) adjusted for sex and family history of type 2 diabetes. Further adjustments included BGA only, concurrent adiposity only (BMI and waist circumference), and BGA plus adiposity. RESULTS—In the basic model, preecl sia (odds ratio 1.78 [95% CI 1.14–2.80]), prepregnancy BMI ≥25 kg/m2 (1.90 [1.45–2.47]), maternal smoking (1.33 [1.04–1.71]), and manual SEP (1.87 [1.36–2.58]) were independently associated with A1C at 45 years of age. Adjustment for BGA had little impact on the prenatal factors/A1C associations, whereas adjustment for adult adiposity at 45 years substantially reduced associations for prepregnancy BMI, smoking during pregnancy, and SEP. CONCLUSIONS—Prenatal exposures were related to blood glucose levels in mid-adulthood. Associations for several prenatal factors were largely mediated through adult adiposity but surprisingly not through birth weight. Prenatal exposures are likely to have the strongest effect on glucose metabolism indirectly through their influence on adiposity.
Publisher: Springer Science and Business Media LLC
Date: 07-04-2013
DOI: 10.1038/NG.2606
Publisher: MDPI AG
Date: 30-12-2020
DOI: 10.3390/NU13010109
Abstract: The relationship between depression and vitamin D deficiency is complex, with evidence mostly from studies affected by confounding and reverse causality. We examined the causality and direction of the relationship between 25-hydroxyvitamin D (25(OH)D) and depression in bi-directional Mendelian randomization (MR) analyses using information from up to 307,618 white British participants from the UK Biobank and summary results from the SUNLIGHT (n = 79,366) and Psychiatric Genomics consortia (PGC 113,154 cases and 218,523 controls). In observational analysis, the odds of depression decreased with higher 25(OH)D concentrations (adjusted odds ratio (OR) per 50% increase 0.95, 95%CI 0.94–0.96). In MR inverse variance weighted (IVW) using the UK Biobank, there was no association between genetically determined serum 25(OH)D and depression (OR per 50% higher 0.97, 95%CI 0.90–1.05) with consistent null association across all MR approaches and in data from PGC consortium. In contrast, genetic liability to depression was associated with lower 25(OH)D concentrations (MR IVW −3.26%, −4.94%–−1.55%), with the estimates remaining generally consistent after meta-analysing with the consortia. In conclusion, we found genetic evidence for a causal effect of depression on lower 25(OH)D concentrations, however we could not confirm a beneficial effect of nutritional vitamin D status on depression risk.
Publisher: MDPI AG
Date: 20-10-2022
DOI: 10.3390/NU14204408
Abstract: Twin studies suggest a considerable genetic contribution to the variability in 25-hydroxyvitamin D (25(OH)D) concentrations, reporting heritability estimates up to 80% in some studies. While genome-wide association studies (GWAS) suggest notably lower rates (13–16%), they have identified many independent variants that associate with serum 25(OH)D concentrations. These discoveries have provided some novel insight into the metabolic pathway, and in this review we outline findings from GWAS studies to date with a particular focus on 35 variants which have provided replicating evidence for an association with 25(OH)D across independent large-scale analyses. Some of the 25(OH)D associating variants are linked directly to the vitamin D metabolic pathway, while others may reflect differences in storage capacity, lipid metabolism, and pathways reflecting skin properties. By constructing a genetic score including these 25(OH)D associated variants we show that genetic differences in 25(OH)D concentrations persist across the seasons, and the odds of having low concentrations ( nmol/L) are about halved for in iduals in the highest 20% of vitamin D genetic score compared to the lowest quintile, an impact which may have notable influences on retaining adequate levels. We also discuss recent studies on personalized approaches to vitamin D supplementation and show how Mendelian randomization studies can help inform public health strategies to reduce adverse health impacts of vitamin D deficiency.
Publisher: Public Library of Science (PLoS)
Date: 11-2011
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000332072
Abstract: Circulating maternal concentrations of hormonally active vitamin D [calcitriol, 1,25(OH) sub /sub D] rise early in the first trimester, doubling by the end of the third trimester. The early rise in calcitriol is believed to be necessary for enabling the immunological adaptation by the mother required for the maintenance of a normal pregnancy. This immunological adaptation is characterized by downregulation of the T helper type 1 (Th1) cytokine responses and a shift towards domination by the Th2 type responses. Attenuation of the Th1-mediated immune response is one of the influences of calcitriol on regulatory T cell activity and dendritic cell maturation. There is accumulating evidence that vitamin D supplementation may be able to prevent the immune maladaptation and loss of tolerance that occur in preecl sia, with evidence for an association obtained from various types of observational studies and clinical trials. There is also evidence from observational studies for potential long-term programming effects of vitamin D supplementation on immunological diseases (such as type 1 diabetes and allergic diseases), with evidence supporting the role of active vitamin D as a potent immunomodulator. This paper highlights the complex effects of active vitamin D on immunomodulation with long-term implications for the risk of immunological diseases. It is suggested that it is essential to avoid vitamin D deficiency during pregnancy, and while accumulating evidence suggests important benefits of further increases in the intake, further research is required to fully establish the influence of high dosages.
Publisher: Public Library of Science (PLoS)
Date: 31-07-2014
Publisher: Springer Science and Business Media LLC
Date: 30-10-2014
Publisher: Public Library of Science (PLoS)
Date: 21-05-2012
Publisher: Oxford University Press (OUP)
Date: 17-07-2018
Abstract: This review was conducted to clarify both the complex interrelationship between adiposity and vitamin D and the clinical implications of vitamin D status on metabolic abnormalities associated with obesity. Obesity increases the risk of vitamin D deficiency, a finding consistently reported across all ages and in different population groups. According to genetic studies, this is driven by the effect of higher adiposity, which causes a reduction in circulating concentrations of 25-hydroxyvitamin D [25(OH)D, used as an indicator of vitamin D status]. Conversely, higher concentrations of 25(OH)D do not appear to affect the risk of obesity. Evidence from clinical trials using vitamin D supplementation to achieve weight reduction is limited. Some trials, however, have suggested that concomitant supplementation with vitamin D and calcium potentially reduces central fat deposits, especially in in iduals with low dietary calcium intakes. Adiposity has important implications for the efficacy of vitamin D supplementation, and increases in 25(OH)D concentrations are generally lower in obese than in normal-weight in iduals. Active hormonal vitamin D has many mechanistic effects, both physiologically and biochemically, that could counteract the harmful effects of obesity on metabolism and reduce the risks of metabolic abnormalities and tissue damage consequent to adiposity. Whether improvements in the overall obesogenic metabolic profile can be achieved by vitamin D supplementation, however, is still unknown.
Publisher: Springer Science and Business Media LLC
Date: 09-04-2013
DOI: 10.1038/IJO.2013.40
Publisher: Elsevier BV
Date: 09-2020
Publisher: Springer Science and Business Media LLC
Date: 04-2023
DOI: 10.1038/S41588-023-01343-9
Abstract: The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration ( n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed seven associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles ( n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal–fetal relationship between gestational duration and birth weight.
Publisher: Springer Science and Business Media LLC
Date: 08-09-2021
Publisher: Elsevier BV
Date: 05-2021
Publisher: Springer Science and Business Media LLC
Date: 09-10-2018
Publisher: Oxford University Press (OUP)
Date: 29-06-2011
DOI: 10.1093/QJMED/HCR101
Publisher: Springer Science and Business Media LLC
Date: 24-04-2014
Publisher: Springer Science and Business Media LLC
Date: 24-05-2021
DOI: 10.1038/S41366-021-00841-2
Abstract: High milk intake has been associated with cardio-metabolic risk. We conducted a Mendelian Randomization (MR) study to obtain evidence for the causal relationship between milk consumption and cardio-metabolic traits using the lactase persistence ( LCT -13910 C T, rs4988235) variant as an instrumental variable. We tested the association of LCT genotype with milk consumption (for validation) and with cardio-metabolic traits (for a possible causal association) in a meta-analysis of the data from three large-scale population-based studies (1958 British Birth Cohort, Health and Retirement study, and UK Biobank) with up to 417,236 participants and using summary statistics from consortia meta-analyses on intermediate traits ( N = 123,665–697,307) and extended to cover disease endpoints ( N = 86,995–149,821). In the UK Biobank, carriers of ‘T’ allele of LCT variant were more likely to consume milk ( P = 7.02 × 10 −14 ). In meta-analysis including UK Biobank, the 1958BC, the HRS, and consortia-based studies, under an additive model, ‘T’ allele was associated with higher body mass index (BMI) ( P meta-analysis = 4.68 × 10 −12 ) and lower total cholesterol (TC) ( P = 2.40 × 10 −36 ), low-density lipoprotein cholesterol (LDL-C) ( P = 2.08 × 10 −26 ) and high-density lipoprotein cholesterol (HDL-C) ( P = 9.40 × 10 −13 ). In consortia meta-analyses, ‘T’ allele was associated with a lower risk of coronary artery disease (OR:0.86, 95% CI:0.75–0.99) but not with type 2 diabetes (OR:1.06, 95% CI:0.97–1.16). Furthermore, the two-s le MR analysis showed a causal association between genetically instrumented milk intake and higher BMI ( P = 3.60 × 10 −5 ) and body fat (total body fat, leg fat, arm fat and trunk fat P 1.37 × 10 −6 ) and lower LDL-C ( P = 3.60 × 10 −6 ), TC ( P = 1.90 × 10 −6 ) and HDL-C ( P = 3.00 × 10 −5 ). Our large-scale MR study provides genetic evidence for the association of milk consumption with higher BMI but lower serum cholesterol levels. These data suggest no need to limit milk intakes with respect to cardiovascular disease risk, with the suggested benefits requiring confirmation in further studies.
Publisher: Wiley
Date: 11-06-2023
DOI: 10.1111/ECI.14037
Abstract: Cancer is a leading cause of morbidity and mortality worldwide, and better understanding of the risk factors could enhance prevention. We conducted a hypothesis‐free analysis combining machine learning and statistical approaches to identify cancer risk factors from 2828 potential predictors captured at baseline. There were 459,169 UK Biobank participants free from cancer at baseline and 48,671 new cancer cases during the 10‐year follow‐up. Logistic regression models adjusted for age, sex, ethnicity, education, material deprivation, smoking, alcohol intake, body mass index and skin colour (as a proxy for sun sensitivity) were used for obtaining adjusted odds ratios, with continuous predictors presented using quintiles (Q). In addition to smoking, older age and male sex, positively associating features included several anthropometric characteristics, whole body water mass, pulse, hypertension and biomarkers such as urinary microalbumin (Q5 vs. Q1 OR 1.16, 95% CI = 1.13–1.19), C‐reactive protein (Q5 vs. Q1 OR 1.20, 95% CI = 1.16–1.24) and red blood cell distribution width (Q5 vs. Q1 OR 1.18, 95% CI = 1.14–1.21), among others. High‐density lipoprotein cholesterol (Q5 vs. Q1 OR 0.84, 95% CI = 0.81–0.87) and albumin (Q5 vs. Q1 OR 0.84, 95% CI = 0.81–0.87) were inversely associated with cancer. In sex‐stratified analyses, higher testosterone increased the risk in females but not in males (Q5 vs. Q1 OR females 1.23, 95% CI = 1.17–1.30). Phosphate was associated with a lower risk in females but a higher risk in males (Q5 vs. Q1 OR females 0.94, 95% CI = 0.90–0.99 vs. OR males 1.09, 95% CI 1.04–1.15). This hypothesis‐free analysis suggests personal characteristics, metabolic biomarkers, physical measures and smoking as important predictors of cancer risk, with further studies needed to confirm causality and clinical relevance.
Publisher: BMJ
Date: 10-2014
DOI: 10.1136/BMJOPEN-2014-006141
Abstract: To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. The analytic s le included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.
Publisher: Elsevier BV
Date: 02-2017
Publisher: Wiley
Date: 04-08-2007
DOI: 10.1111/J.1398-9995.2007.01437.X
Abstract: In addition to its role in the regulation of calcium metabolism, vitamin D has a number of immunological effects. Several studies in children found an effect of oral supplementation on allergic sensitization but so far there are no population-based studies of vitamin D serum levels. We therefore examined 25(OH)-D(3) status in 18,224 adults of the Third National Health and Nutrition Examination Survey. There was no effect on sensitization to a single allergen while the prevalence of allergic rhinitis increased across quartile groups of current vitamin D serum levels. The association could be due to unrecognized confounding, however, could also point towards an altered metabolism or an increased sensitivity to vitamin D in allergic patients.
Publisher: Public Library of Science (PLoS)
Date: 07-2015
Publisher: Springer Science and Business Media LLC
Date: 21-05-2022
DOI: 10.1038/S41598-022-12198-1
Abstract: We assigned 329,908 UK Biobank participants into six subgroups based on a self-organizing map of 51 biochemical measures (blinded for clinical outcomes). The subgroup with the most favorable metabolic traits was chosen as the reference. Hazard ratios (HR) for incident disease were modeled by Cox regression. Enrichment ratios (ER) of incident multi-morbidity versus randomly expected co-occurrence were evaluated by permutation tests ER is like HR but captures co-occurrence rather than event frequency. The subgroup with high urinary excretion without kidney stress (HR = 1.24) and the subgroup with the highest apolipoprotein B and blood pressure (HR = 1.52) were associated with ischemic heart disease (IHD). The subgroup with kidney stress, high adiposity and inflammation was associated with IHD (HR = 2.11), cancer (HR = 1.29), dementia (HR = 1.70) and mortality (HR = 2.12). The subgroup with high liver enzymes and triglycerides was at risk of diabetes (HR = 15.6). Multimorbidity was enriched in metabolically favorable subgroups (3.4 ≤ ER ≤ 4.0) despite lower disease burden overall the relative risk of co-occurring disease was higher in the absence of obvious metabolic dysfunction. These results provide synergistic insight into metabolic health and its associations with cardiovascular disease in a large population s le.
Publisher: Proceedings of the National Academy of Sciences
Date: 31-10-2016
Abstract: In iduals with more education tend to live longer. Genetic variants have been discovered that predict educational attainment. We tested whether a “polygenic score” based on these genetic variants could make predictions about people’s lifespan. We used data from three cohort studies (including ,000 participants) to examine the link between offspring polygenic score for education and parental longevity. Across the studies, we found that participants with more education-linked genetic variants had longer-living parents compared with those with the lowest genetic education scores, those with the highest scores had parents who lived on average 6 months longer. This finding suggests the hypothesis that part of the ultimate explanation for the extended longevity of better-educated people is an underlying, quantifiable, genetic propensity.
Publisher: MDPI AG
Date: 21-09-2022
DOI: 10.3390/NU14193907
Abstract: Genetic susceptibility and lifestyle affect the risk of dementia but there is little direct evidence for their associations with preclinical changes in brain structure. We investigated the association of genetic dementia risk and healthy lifestyle with brain morphometry, and whether effects from elevated genetic risk are modified by lifestyle changes. We used prospective data from up to 25,894 UK Biobank participants (median follow-up of 8.8 years), and defined healthy lifestyle according to American Heart Association criteria as BMI 30, no smoking, healthy diet and regular physical activity). Higher genetic risk was associated with lower hippoc al volume (beta −0.16 cm3, 95% CI −0.22, −0.11) and total brain volume (−4.34 cm3, 95% CI −7.68, −1.01) in participants aged ≥60 years but not years. Healthy lifestyle was associated with higher total brain, grey matter and hippoc al volumes, and lower volume of white matter hyperintensities, with no effect modification by age or genetic risk. In conclusion, adverse effects of high genetic risk on brain health were only found in older participants, while adhering to healthy lifestyle recommendations is beneficial regardless of age or genetic risk.
Publisher: Elsevier BV
Date: 06-2023
Publisher: American Diabetes Association
Date: 12-2000
DOI: 10.2337/DIACARE.23.12.1755
Abstract: OBJECTIVE: The purpose of the present study was to evaluate the effect of obesity and linear growth on the risk of developing type 1 diabetes in children. RESEARCH DESIGN AND METHODS: The study population consists of all diabetic children & years of age diagnosed from September 1986 to April 1989 in Finland and their birth date- and sex-matched population-based control subjects. Growth data were obtained from well-baby clinics and school health care units for 586 diabetic and 571 control subjects, resulting in a total of 18,823 paired weight-height observations. RESULTS: Both boys and girls who developed type 1 diabetes were heavier and taller throughout childhood than control children. A 10% unit increment in relative weight was associated with a 50-60% increase in the risk of type 1 diabetes before 3 years of age and a 20-40% increase from 3 to 10 years of age. The increase in risk of type 1 diabetes for 1 SD score increment in relative height was 20-30%. Obesity (relative weight & 120%) after 3 years of age was associated with a more than twofold risk of developing type 1 diabetes. CONCLUSIONS: The present observation that obesity and rapid linear growth are risk factors for type 1 diabetes in children indicates that the increase in the prevalence of obesity and secular growth that has occurred in most industrialized countries over the last decades may be involved in the increase in type 1 diabetes incidence simultaneously observed in many countries.
Publisher: Wiley
Date: 23-07-2010
DOI: 10.1111/J.1463-1326.2010.01211.X
Abstract: There has been an important shift in the views about the actions of vitamin D during the past decade. In addition to its well-established role in the regulation of calcium metabolism, vitamin D deficiency has been associated with the risk of several extra-skeletal diseases, including type 1 diabetes among other chronic conditions. It is notable that 1,25(OH)(2)D is known to regulate the expression of over 200 different genes, including the ones related to apoptosis and immune modulation. Increased vitamin D intake is currently considered as one of the most promising candidates for the prevention of type 1 diabetes, and it has been suggested that changes in vitamin D intake during the past decades have contributed to the recent trends in the incidence of the disease. This study reviews the evidence for the role of vitamin D in type 1 diabetes development, demonstrating that support has been obtained from various lines of investigation and that the possible biological mechanisms are plausible. However, much of the evidence has been obtained from animal experiments or observational studies in humans and there is an urgent need for well-designed, randomized, controlled trials to show whether the observed associations are indeed causal.
Publisher: American Academy of Pediatrics (AAP)
Date: 05-2008
Abstract: OBJECTIVE. Child abuse has been associated with poorer physical health in adulthood, but less is known about childhood adversity more broadly, including neglect and family problems, or the pathways from adversity to adult disease. We have examined how different stressful emotional or neglectful childhood adversities are related to adiposity and glucose control in midadulthood, taking into account childhood factors, and whether the relationships are mediated by adult health behaviors and socioeconomic position. METHODS. This was a prospective longitudinal study of 9310 members of the 1958 British birth cohort who participated in a biomedical interview at 45 years of age. Primary outcomes consisted of continuous measures of BMI, waist circumference, and glycosylated hemoglobin at 45 years and categorical indicators: total obesity (BMI ≥ 30), central obesity (waist circumference: ≥102 cm for men and ≥88 cm for women), and glycosylated hemoglobin level of ≥6. RESULTS. The risk of obesity increased by 20% to 50% for several adversities (physical abuse, verbal abuse, witnessed abuse, humiliation, neglect, strict upbringing, physical punishment, conflict or tension, low parental aspirations or interest in education, hardly takes outings with parents, and father hardly reads to child). Adversities with the strongest associations with adiposity (eg, physical abuse) tended to be associated with glycosylated hemoglobin levels of ≥6, but in most cases associations were explained by adjustment for adulthood mediators such as adiposity. Effects of other adversities reflecting less severe emotional neglect and family environment were largely explained by childhood socioeconomic factors. CONCLUSIONS. Some childhood adversities increase the risk of obesity in adulthood and thereby increase the risk for type 2 diabetes. Research is needed to understand the interrelatedness of adversities, the social context of their occurrence, and trajectories from adversity to adult disease.
Publisher: Wiley
Date: 09-1998
DOI: 10.1002/(SICI)1096-9136(199809)15:9<730::AID-DIA646>3.0.CO;2-C
Publisher: Informa UK Limited
Date: 15-06-2011
DOI: 10.3109/03014460.2011.591827
Abstract: Parent-offspring adiposity associations are well-established: offspring of obese parents have elevated risks of overweight/obesity. The aim of studies based on the 1958 British birth cohort has been to gain insights into explanations of these associations, such as whether parent-offspring BMI associations are due to offspring lifestyles or depend on socio-economic conditions. All major studies on intergenerational adiposity associations in the three generations of the 1958 birth cohort were reviewed. In addition, BMI data for parents (G1) and the cohort (G2) were analysed stratified by social class. BMI of G1 and G2 were correlated both when offspring were children and in mid-adulthood: a 1 kg/m(2) higher parental BMI was associated with an average 0.24-0.35 kg/m(2) higher offspring (mothers/fathers vs sons/daughters) BMI at 45 years. Associations were little affected by adjustment for lifestyle and socio-economic factors, but varied by social class: average BMI gain in offspring relative to parents was greater in lower classes, e.g. for males vs fathers by 3.6 and 2.5 kg/m(2) in classes IV&V and I&II, respectively. Parent-offspring BMI associations were stronger for recent (G2 and G3) than older (G1 and G2) generations. Parent-offspring associations in BMI were not explained by offspring lifestyles, but varied over successive generations and by social class, suggesting that intergenerational transmission of adiposity at a population level is modifiable rather than immutable.
Publisher: Oxford University Press (OUP)
Date: 20-01-2016
DOI: 10.1093/AJE/KWV203
Publisher: The Endocrine Society
Date: 12-2007
DOI: 10.1210/JC.2007-1279
Abstract: An automated application of Immunodiagnostic Systems Limited (IDS) OCTEIA 25-hydroxyvitamin D [25(OH)D] enzyme immunoassay was developed for analyses of 25(OH)D in more than 7000 participants of the 1958 cohort. Variation between 25(OH)D assays h ers between-study comparisons and the definition of relevant cutoffs for hypovitaminosis D. The objective of the study was to evaluate the importance of assay variation on the estimated prevalence of hypovitaminosis D and assess the use of statistical harmonization to overcome the observed differences. Agreement analyses were performed between two commercial 25(OH)D assays (IDS enzyme immunoassay and Diasorin RIA), with validation using performance data from Vitamin D External Quality Assessment Scheme (DEQAS). The study was conducted in England, Scotland, and Wales. Members of the 1958 British birth cohort participated in the study. 25(OH)D was measured both by IDS and Diasorin RIA in 781 s les. Additional quality control data were obtained through participation in DEQAS (five distributions throughout the survey). Average 25(OH)D concentrations by IDS were -15.7 and -13.7 nmol/liter lower, compared with Diasorin or DEQAS mean, respectively (both P or= 0.21 for comparison of IDS with Diasorin or DEQAS) and estimates for hypovitaminosis D obtained by IDS were similar to Diasorin. Differences between assays have implications for public health messages about hypovitaminosis D. Harmonization of results with DEQAS enabled the use of previously determined cutoffs for hypovitaminosis D.
Publisher: BMJ
Date: 18-10-2003
Publisher: Springer Science and Business Media LLC
Date: 07-10-2014
DOI: 10.1038/MP.2014.107
Publisher: European Respiratory Society (ERS)
Date: 2020
DOI: 10.1183/23120541.00343-2019
Abstract: Few studies have examined the contribution of life-course factors in explaining familial aggregation of chronic lung conditions. Using data from the 1958 British Birth Cohort, a life-course approach was used to examine whether, and how, exposure to risk factors through one's life explained the association between parental respiratory disease history and symptomatic airflow obstruction (AO). Cohort participants (n=6212) were characterised in terms of parental respiratory disease history and symptomatic AO at 45 years. Life-course factors ( e.g. smoking, asthma and early-life factors) were operationalised as life period-specific and cumulative measures. Logistic regression and path analytic models predicting symptomatic AO adjusted for parental respiratory disease history were used to test different life-course models (critical period, accumulation- and chain-of-risks models). While some life-course factors ( e.g. childhood passive smoking and occupational exposure) were in idually associated with parental respiratory disease history and symptomatic AO, asthma (OR 6.44, 95% CI 5.01–8.27) and persistent smoking in adulthood (OR 5.42, 95% CI 4.19–7.01) had greater impact on the association between parental respiratory disease history and symptomatic AO. A critical period model provided a better model fit compared with an accumulation-of-risk model and explained 57% of the effect of parental respiratory disease history on symptomatic AO. Adulthood asthma and smoking status explained around half of the effect of parental respiratory disease history on chronic obstructive pulmonary disease. Beyond smoking history, the combination of parental respiratory disease history and adulthood asthma may provide an opportunity for early diagnosis and intervention.
Publisher: Springer Science and Business Media LLC
Date: 05-2019
Publisher: Springer Science and Business Media LLC
Date: 02-09-2200
DOI: 10.1038/S41467-019-11881-8
Abstract: The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration the association is replicated in 9,291 additional infants (combined P = 3.96 × 10 −14 ). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.
Publisher: American Diabetes Association
Date: 23-04-2011
DOI: 10.2337/DB10-1656
Abstract: Vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] & nmol/L) is commonly reported in both children and adults worldwide, and growing evidence indicates that vitamin D deficiency is associated with many extraskeletal chronic disorders, including the autoimmune diseases type 1 diabetes and multiple sclerosis. We measured 25(OH)D concentrations in 720 case and 2,610 control plasma s les and genotyped single nucleotide polymorphisms from seven vitamin D metabolism genes in 8,517 case, 10,438 control, and 1,933 family s les. We tested genetic variants influencing 25(OH)D metabolism for an association with both circulating 25(OH)D concentrations and disease status. Type 1 diabetic patients have lower circulating levels of 25(OH)D than similarly aged subjects from the British population. Only 4.3 and 18.6% of type 1 diabetic patients reached optimal levels (≥75 nmol/L) of 25(OH)D for bone health in the winter and summer, respectively. We replicated the associations of four vitamin D metabolism genes (GC, DHCR7, CYP2R1, and CYP24A1) with 25(OH)D in control subjects. In addition to the previously reported association between type 1 diabetes and CYP27B1 (P = 1.4 × 10−4), we obtained consistent evidence of type 1 diabetes being associated with DHCR7 (P = 1.2 × 10−3) and CYP2R1 (P = 3.0 × 10−3). Circulating levels of 25(OH)D in children and adolescents with type 1 diabetes vary seasonally and are under the same genetic control as in the general population but are much lower. Three key 25(OH)D metabolism genes show consistent evidence of association with type 1 diabetes risk, indicating a genetic etiological role for vitamin D deficiency in type 1 diabetes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-05-2021
DOI: 10.1097/GME.0000000000001781
Abstract: To investigate vitamin D status in women with the onset of the climacteric phase by age 46 as both early menopause and inadequate vitamin D status may increase the risk of adverse health outcomes. A cross-sectional study included 2,544, 46-year-old women from a birth cohort. Women were ided into the following two groups according to their menstrual history and follicle-stimulating hormone (FSH) concentration: 1) climacteric (FSH ≥25 IU/L and amenorrhea ≥4 mo, n = 351) and 2) preclimacteric women (FSH IU/L and having regular/irregular menstrual cycles, n = 2,193). Serum 25-hydroxyvitamin D (25(OH)D) concentrations were compared between the groups. A linear regression model was performed to investigate which factors are associated with 25(OH)D status. Mean serum 25(OH)D concentrations were higher in climacteric compared with preclimacteric women (68.1 ± 19.8 nmol/L vs 65.2 ± 19.3 nmol/L, P = 0.01). However, in the linear regression model, climacteric status was not associated with 25(OH)D status (multivariable adjusted mean difference 4.5 nmol/L, 95% confidence interval −1.4 to 10.4, P = 0.137). A total of 76 of the climacteric women were using systemic estrogen hormone therapy (HT). In a subanalysis, including only climacteric women, the use of HT was associated with higher 25(OH)D status (multivariable adjusted mean difference 5.9 nmol/L, 95% confidence interval 1.3-10.5, P = 0.013). The onset of the climacteric phase by age 46 was not associated with inadequate 25(OH)D concentrations, whereas HT use was associated with higher 25(OH)D status in women with early-onset climacterium.
Publisher: American Diabetes Association
Date: 19-02-2009
DOI: 10.2337/DB08-1739
Abstract: Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight. We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring. We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11–31], P = 2 × 10−5, and 14 g [4–23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39–120) lighter at birth than the 8% carrying none (Ptrend = 5 × 10−7). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus. Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype.
Publisher: Public Library of Science (PLoS)
Date: 06-06-2013
Publisher: Research Square Platform LLC
Date: 16-12-2021
DOI: 10.21203/RS.3.RS-1129252/V1
Abstract: Even though physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Here, we combine data for up to 674,980 in iduals from 51 studies in a trans-ancestry meta-analysis of genome-wide association studies for self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA) leisure screen time (LST) sedentary commuting and sedentary behavior at work. We identify 99 loci that associate with at least one trait. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. Molecular dynamics simulations suggest that the Glu to Ala substitution encoded by rs2229456 (ACTN3) – associated with more MVPA – disrupts salt bridge interactions and makes the alpha actinin 3 filaments more flexible. In isolated type II A muscle fibers, the Ala-encoding allele is associated with lower maximal force and power during an isometric contraction, suggesting protection from exercise-induced muscle damage. Finally, Mendelian Randomization analyses show that the causal effect of LST on BMI is 2-3 times larger than the effect of body mass index (BMI) on LST, and that beneficial effects of LST and MVPA on several risk factors and diseases are mediated or confounded by BMI. Taken together, our results provide mechanistic insights into the regulation of MVPA and into the role of LST and MVPA in disease prevention. These insights may facilitate the development of tailored physical activity interventions.
Publisher: Oxford University Press (OUP)
Date: 24-11-2015
DOI: 10.1093/HMG/DDV472
Publisher: Elsevier
Date: 2018
Publisher: Elsevier BV
Date: 04-1995
DOI: 10.1016/S0002-9149(99)80416-0
Abstract: Amyl nitrite may be used to provoke latent gradients in patients with hypertrophic cardiomyopathy (HC) without significant resting outflow tract gradients, but afterload reduction may not be comparable to a more physiologic stressor such as symptom-limited exercise testing. This study compared the ability of amyl nitrite and exercise testing to provoke outflow tract gradients in 57 patients (40 men and 17 women, mean age +/- SD 49 +/- 16 years) with HC (septal thickness 19 +/- 5 mm, average resting gradient 13 +/- 10 mm Hg) who underwent echocardiography at rest, after amyl nitrite inhalation, and after maximal exercise. No significant gradient (< 50 mm Hg) was induced after either provocation in 26 patients (46%) in 15 patients (26%), inducibility was achieved after both stressors, in 6 (11%) after exercise only, and in 10 (18%) after amyl only. Patients with amyl-induced gradients differed from those in whom gradients were noninducible on the basis of smaller outflow tract dimensions (p < 0.001), larger resting gradients (p < 0.001), and a greater prevalence of "septal bulge" morphology (p = 0.02). Those with exercise-induced gradients were able to attain a greater workload (p = 0.07), have larger resting gradients (p = 0.02), and also tended to have a septal bulge morphology (p < or = 0.01). Although outflow tract obstruction increased to similar levels after amyl nitrite (49 +/- 39 mm Hg) and symptom-limited exercise (47 +/- 39 mm Hg), gradients induced by exercise and amyl correlated poorly (r = 0.54).(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Elsevier BV
Date: 2022
Publisher: Wiley
Date: 18-06-2015
DOI: 10.1002/AJMG.B.32333
Abstract: In idual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome-wide approaches of aggressive behavior in children. We analyzed data from nine population-based studies and assessed aggressive behavior using well-validated parent-reported questionnaires. This is the largest s le exploring children's aggressive behavior to date (N = 18,988), with measures in two developmental stages (N = 15,668 early childhood and N = 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of children's aggressive behavior based on genome-wide SNP information, using genome-wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi-Poisson regression approach, capturing the highly right-skewed distribution of aggressive behavior. Third, we performed meta-analyses of genome-wide associations for both the total age-mixed s le and the two developmental stages. Finally, we performed a gene-based test using the summary statistics of the total s le. GCTA quantified variance tagged by common SNPs (10-54%). The meta-analysis of the total s le identified one region in chromosome 2 (2p12) at near genome-wide significance (top SNP rs11126630, P = 5.30 × 10(-8) ). The separate meta-analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene-based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning. © 2015 Wiley Periodicals, Inc.
Publisher: Oxford University Press (OUP)
Date: 07-06-2007
DOI: 10.1093/AJE/KWM054
Abstract: The authors have investigated associations between offspring size at birth and parental cardiovascular disease mortality among 12,086 mothers and 6,936 fathers of participants in the British 1958 birth cohort. Birth weight was inversely associated with all-cause mortality and cardiovascular mortality in both mothers and fathers. The adjusted hazard ratio of cardiovascular disease mortality for a 1-standard deviation increase in offspring birth weight in mothers was 0.87 (95% confidence interval (CI): 0.82, 0.93) and in fathers was 0.94 (95% CI: 0.89, 0.99). The association was not specific for cardiovascular disease. In fathers, similar weak associations with violent and accidental deaths, stomach cancer, and alcohol- and smoking-related outcomes were found. Weak associations for these outcomes were also found for mothers, but the magnitude of the association with cardiovascular disease was greater than with any other outcomes. In a meta-analysis pooling results from this study with six others, the adjusted hazard ratio of cardiovascular disease mortality among mothers was 0.75 (95% CI: 0.67, 0.84) and that among fathers was 0.93 (95% CI: 0.91, 0.95), with evidence that the difference in effect between mothers and fathers was not due to chance (p < 0.001). The weak association of offspring birth weight with cardiovascular disease in fathers may be due to residual confounding by factors such as socioeconomic position and smoking that they share with the offspring's mother and that would therefore be associated with low offspring birth weight as well as adverse outcomes in the father. The stronger association in mothers is consistent with intergenerational effects on intrauterine growth and with the fetal origins hypothesis.
Publisher: Wiley
Date: 05-2004
Publisher: American Diabetes Association
Date: 06-2000
DOI: 10.2337/DIABETES.49.6.912
Abstract: The evidence for the putative role of cow's milk in the development of type 1 diabetes is controversial. We studied infant feeding patterns and childhood diet by structured questionnaire (n = 725) and HLA-DQB1 genotype by a polymerase chain reaction-based method (n = 556) in siblings of affected children and followed them for clinical type 1 diabetes. In a nested case-control design in a population who had both dietary and genetic data available, we selected as cases those siblings who progressed to clinical diabetes during the follow-up period (n = 33). For each case, we chose as matched control subjects siblings who fulfilled the following criteria: same sex, age within 1 year, not from the same family, the start of the follow-up within 6 months of that of the respective case, and being at risk for type 1 diabetes at the time the case presented with that disease (n = 254). The median follow-up time was 9.7 years (range 0.2-11.3). Early age at introduction of cow's milk supplements was not significantly associated with progression to clinical type 1 diabetes (relative risk adjusted for matching factors, maternal education, maternal and child's ages, childhood milk consumption, and genetic susceptibility markers was 1.60 [95% CI 0.5-5.1]). The estimated relative risk of childhood milk consumption for progression to type 1 diabetes was 5.37 (1.6-18.4) when adjusted for the matching and aforementioned sociodemographic factors, age at introduction of supplementary milk feeding, as well as for genetic susceptibility markers. In conclusion, our results provide support for the hypothesis that high consumption of cow's milk during childhood can be diabetogenic in siblings of children with type 1 diabetes. However, further studies are needed to assess the possible interaction between genetic disease susceptibility and dietary exposures in the development of this disease.
Publisher: Oxford University Press (OUP)
Date: 25-04-2014
DOI: 10.1093/HMG/DDU150
Publisher: BMJ
Date: 03-11-2001
Publisher: Springer Science and Business Media LLC
Date: 14-01-2019
Publisher: American Diabetes Association
Date: 10-2007
DOI: 10.2337/DB07-0652
Abstract: OBJECTIVE—Epidemiological studies have linked vitamin D deficiency with the susceptibility to type 1 diabetes. Higher levels of the active metabolite 1α,25-dihydroxyvitamin D (1α,25(OH)2D) could protect from immune destruction of the pancreatic β-cells. 1α,25(OH)2D is derived from its precursor 25-hydroxyvitamin D by the enzyme 1α-hydroxylase encoded by the CYP27B1 gene and is inactivated by 24-hydroxylase encoded by the CYP24A1 gene. Our aim was to study the association between the CYP27B1 and CYP24A1 gene polymorphisms and type 1 diabetes. RESEARCH DESIGN AND METHODS—We studied 7,854 patients with type 1 diabetes, 8,758 control subjects from the U.K., and 2,774 affected families. We studied four CYP27B1 variants, including common polymorphisms −1260C& A (rs10877012) and +2838T& C (rs4646536) and 16 tag polymorphisms in the CYP24A1 gene. RESULTS—We found evidence of association with type 1 diabetes for CYP27B1 −1260 and +2838 polymorphisms, which are in perfect linkage disequilibrium. The common C allele of CYP27B1 −1260 was associated with an increased disease risk in the case-control analysis (odds ratio for the C/C genotype 1.22, P = 9.6 × 10−4) and in the fully independent collection of families (relative risk for the C/C genotype 1.33, P = 3.9 × 10−3). The combined P value for an association with type 1 diabetes was 3.8 × 10−6. For the CYP24A1 gene, we found no evidence of association with type 1 diabetes (multilocus test, P = 0.23). CONCLUSIONS—The present data provide evidence that common inherited variation in the vitamin D metabolism affects susceptibility to type 1 diabetes.
Publisher: BMJ
Date: 03-2017
Publisher: Springer Science and Business Media LLC
Date: 09-2022
DOI: 10.1038/S41588-022-01165-1
Abstract: Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 in iduals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type II A muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.
Publisher: American Diabetes Association
Date: 12-1999
DOI: 10.2337/DIACARE.22.12.1961
Abstract: OBJECTIVE: To evaluate whether the increased risk of type 1 diabetes conferred by an early introduction of cow's milk supplements can be mediated by accelerated growth in formula-fed infants. RESEARCH DESIGN AND METHODS: All children & or = 14 years of age who were diagnosed with type 1 diabetes from September 1986 to April 1989 were invited to participate in the study. Birth date- and sex-matched control children were randomly selected from the Finnish Population Registry. At least three weight measurements from the first year of life were obtained for 435 full-term diabetic subjects and 386 control subjects from well-baby clinics and school health care units. RESULTS: Increase in body weight was greater in the diabetic girls than in the control girls, and the difference increased from 111 g (95% CI 0-218, P = 0.04) at 1 month of age to 286 g (95% CI 123-450, P = 0.0006) at 7 months. For boys, the difference in weight between the diabetic subjects and the control subjects remained stable during infancy (difference 95 g, 95% CI-2-205, P = 0.09). Increased weight was associated on average with a 1.5-fold risk of type 1 diabetes. Early introduction of formula feeding (& 3 vs. & or = 3 months) was also associated with an increased risk of type 1 diabetes after adjustment for the in idual weight gain curve (adjusted odds ratio 1.53, 95% CI 1.1-2.2). No evidence for interaction was observed. CONCLUSIONS: These observations indicate that an early exposure to cow's milk formula-feeding and rapid growth in infancy are independent risk factors of childhood type 1 diabetes.
Publisher: Public Library of Science (PLoS)
Date: 24-05-2010
Publisher: Cold Spring Harbor Laboratory
Date: 03-02-2021
DOI: 10.1101/2021.02.01.21250893
Abstract: Background: Ischemic heart disease (IHD), diabetes, cancer and dementia share features of age-associated metabolic dysfunction. We hypothesized that metabolic ersity explains the ersity of morbidity later in life. Methods: We analyzed data from the UK Biobank (N = 329,908). A self-organizing map (SOM, an artificial neural network) was trained with 51 metabolic traits adjusted for age and sex. The SOM analyses produced six subgroups that summarized the multi-variable metabolic ersity. The subgroup with the lowest adiposity and disease burden was chosen as the reference. Hazard ratios (HR) were modeled by Cox regression (P 0.0001 unless otherwise indicated). Enrichment of multi-morbidity over random expectation was tested by permutation analysis. Results: The subgroup with the highest sex hormones was not associated with IHD (HR = 1.04, P = 0.14). The subgroup with high urinary excretion without kidney stress (HR = 1.24) and the subgroup with the highest apolipoprotein B and blood pressure (HR = 1.52) were associated with IHD. The subgroup with high adiposity, inflammation and kidney stress was associated with IHD (HR = 2.11), cancer (HR= 1.29), dementia (HR = 1.70) and mortality (HR = 2.12). The subgroup with high triglycerides and liver enzymes was at risk of diabetes (HR = 15.6). Paradoxical enrichment of multimorbidity in young in iduals and in favorable subgroups was observed. Conclusions: These results support metabolic ersity as an explanation to erging morbidity and demonstrate the potential value of population-based metabolic subgroups as public health targets for reducing aggregate burden of chronic diseases in ageing populations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2011
Publisher: Elsevier BV
Date: 09-2020
Publisher: Cambridge University Press (CUP)
Date: 29-11-2020
DOI: 10.1017/S0007114519003076
Abstract: Excessive Ca intakes have been proposed to associate with vascular calcification and a higher risk of prostate cancer. We investigated the associations of supplemental and dietary Ca intake with mortality using data from 497 828 UK Biobank participants. The average follow-up was 4·2 years and 14 255 participants died, 8297 from cancer, 2959 from CVD and 572 from respiratory disease. The use of Ca supplements and milk consumption were associated with differences in mortality in younger (≤65 years) but not in older participants ( years, P interaction ≤ 0·04 for all comparisons). Among participants years, there was an inverse association between Ca supplementation (OR 0·91, 95 % CI 0·83, 0·99) and milk consumption (OR 0·93, 95 % CI 0·86, 1·00) with respect to all-cause mortality. In the same age group, milk drinkers had lower odds of cancer mortality (OR 0·89, 95 % CI 0·80, 0·98) but Ca supplement use was associated with increased odds of respiratory mortality (OR 1·69, 95 % CI 1·16, 2·74). All associations in participants aged ≥65 years were null after full adjustment. In sensitivity analyses stratified by hormone replacement therapy, Ca supplement use was associated with decreased odds of cancer mortality in users but increased risk in other women (OR 0·81, 95 % CI 0·69, 0·94 v . OR 1·17, 95 % CI 1·01, 1·35, respectively). To conclude, we saw little evidence for harm with dietary or supplemental Ca. Further studies are required to confirm the proposed interaction with hormone replacement therapy and to exclude reverse causation as a determinant in the association between Ca supplements and increased risk of respiratory diseases.
Publisher: Springer Science and Business Media LLC
Date: 2014
Publisher: Elsevier BV
Date: 04-2011
Abstract: High birth weight is associated with adult body mass index (BMI). We hypothesized that birth weight and BMI may partly share a common genetic background. The objective was to examine the associations of 12 established BMI variants in or near the NEGR1, SEC16B, TMEM18, ETV5, GNPDA2, BDNF, MTCH2, BCDIN3D, SH2B1, FTO, MC4R, and KCTD15 genes and their additive score with birth weight. A meta-analysis was conducted with the use of 1) the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk, Hertfordshire, Fenland, and European Youth Heart Study cohorts (n(max) = 14,060) 2) data extracted from the Early Growth Genetics Consortium meta-analysis of 6 genome-wide association studies for birth weight (n(max) = 10,623) and 3) all published data (n(max) = 14,837). Only the MTCH2 and FTO loci showed a nominally significant association with birth weight. The BMI-increasing allele of the MTCH2 variant (rs10838738) was associated with a lower birth weight (β ± SE: -13 ± 5 g/allele P = 0.012 n = 23,680), and the BMI-increasing allele of the FTO variant (rs1121980) was associated with a higher birth weight (β ± SE: 11 ± 4 g/allele P = 0.013 n = 28,219). These results were not significant after correction for multiple testing. Obesity-susceptibility loci have a small or no effect on weight at birth. Some evidence of an association was found for the MTCH2 and FTO loci, ie, lower and higher birth weight, respectively. These findings may provide new insights into the underlying mechanisms by which these loci confer an increased risk of obesity.
Publisher: American College of Physicians
Date: 11-2022
DOI: 10.7326/M21-3324
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.PUHE.2004.11.002
Abstract: We recently traced and flagged parents for the participants in the National Child Development Survey (NCDS, 1958 cohort). This paper evaluates the representativeness of the study population and assesses our success in identifying the biological parents. Intergenerational cohort study. Parents for participants in the NCDS (born 1 week in March 1958) were traced and flagged for mortality follow-up (14 334 fathers, 15 076 mothers). Standardized mortality rates (SMRs) were calculated using data from England, Scotland and Wales during corresponding time periods. By 31 December 2003, 6808 fathers and 4148 mothers (born 1890-1943) had died (569 918 and 645 354 years of follow-up, respectively). The overall mortality rate in this parent population was lower compared with the age-, gender-, period- and area-standardized reference rates (SMRs of 83 for fathers and 86 for mothers). Mortality rates for biological parents were higher if cohort members had had non-biological parent figures during the childhood surveys (SMRs of 135 for fathers and 374 for mothers). Parental smoking (in 1974) was strongly associated with lung cancer mortality among biological parents [HR 6.1, 95% confidence intervals (CI) 4.6-8.1 for fathers HR 15.0, 95% CI 9.7-23 for mothers) but not among non-biological parents (HR 2.0, 95% CI 0.8-5.5 HR 1.8, 95% CI 0.4-7.9, respectively) which demonstrates that the tracing of the biological parents had been successful. Mortality is markedly reduced in a cohort of parents compared with the general population. The validity of identification of biological parents is demonstrated by the strong association between smoking and lung cancer.
Publisher: Springer Science and Business Media LLC
Date: 21-06-2022
DOI: 10.1038/S42003-022-03554-Y
Abstract: Hormone-related cancers, including cancers of the breast, prostate, ovaries, uterine, and thyroid, globally contribute to the majority of cancer incidence. We hypothesize that hormone-sensitive cancers share common genetic risk factors that have rarely been investigated by previous genomic studies of site-specific cancers. Here, we show that considering hormone-sensitive cancers as a single disease in the UK Biobank reveals shared genetic aetiology. We observe that a significant proportion of variance in disease liability is explained by the genome-wide single nucleotide polymorphisms (SNPs), i.e., SNP-based heritability on the liability scale is estimated as 10.06% (SE 0.70%). Moreover, we find 55 genome-wide significant SNPs for the disease, using a genome-wide association study. Pair-wise analysis also estimates positive genetic correlations between some pairs of hormone-sensitive cancers although they are not statistically significant. Our finding suggests that heritable genetic factors may be a key driver in the mechanism of carcinogenesis shared by hormone-sensitive cancers.
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.PUHE.2004.11.003
Abstract: This paper describes the methods used to obtain information on mortality and cancer registrations for the parents of the British 1958 birth cohort, in order to create a dataset that can be used to examine intergenerational relationships on health and growth. Intergenerational cohort study. The 1958 cohort includes all births occurring during 1 week in March 1958 in England, Scotland and Wales. For more than four decades of follow-up, information has been collected on cohort members, their parents and children. Information on the National Health Service (NHS) numbers of the parents was not available, but other details were collated for the Office for National Statistics to trace and flag the biological parents of the cohort members. Tracing was successful in 90.2% of fathers (n = 14,334) and 94.9% of mothers (n = 15,076). The greatest success was achieved for parents in families where there was no indication for additional mother or father figures until the child was 16 years old (96.6% of the mothers traced, n = 14,274 94.3% of the fathers traced, n = 13,256). Tracing rates were lower than average in unmarried mothers (59%) and for the small group who were separated, widowed or orced in 1958 (81%) the rates were particularly poor for the corresponding fathers (24.4 and 54.7%, respectively). There were only small variations in tracing rates between different regions of Britain. The tracing rates achieved were generally very high despite the lack of NHS number, especially where there was family stability throughout the childhood of cohort members. Parental status will need to be considered in future studies. With the high tracing rates achieved, the dataset provides an important resource with which to evaluate multigenerational associations with health and development in parents, their offspring and grandchildren.
Publisher: Elsevier BV
Date: 05-2011
Abstract: High vitamin D intake in childhood has been suggested to have an adverse influence on linear growth. In Finland, in the mid-1960s the official recommendation for infant vitamin D supplementation was 2000 IU/d (50 μg/d). We investigated whether high-dose vitamin D supplementation in infancy was associated with subsequent growth in height. We used data from a prospective population-based birth cohort study including all children due to be born in the 2 northernmost provinces in Finland in 1966 (12,058 live-births, coverage 96%). Information on each participant's height was collected at birth and ages 1, 14, and 31 y, as were possible confounding factors (data for analyses available from 10,060 singletons). Information on the frequency and dose of vitamin D supplementation was collected in 1967 when participants were 1 y of age. A weak association was found between frequency of vitamin D supplementation with greater height at age 1 y (P = 0.005), which was explained by birth characteristics and maternal and social factors (adjusted P = 0.34). Neither frequency nor dose of vitamin D supplementation was associated with height at 14 or 31 y (P > 0.13). To conclude, contrary to proposed evidence suggesting that vitamin D has a negative influence on growth rate at a dosage of ~2000 IU/d, supplementation at this level in the Northern Finland Birth Cohort was not associated with reduced height at any age studied.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.JSBMB.2017.01.019
Abstract: Vitamin D deficiency is common in patients with chronic obstructive pulmonary disease (COPD), yet a comprehensive analysis of environmental and genetic determinants of serum 25-hydroxyvitamin D (25[OH]D) concentration in patients with this condition is lacking. We conducted a multi-centre cross-sectional study in 278 COPD patients aged 41-92 years in London, UK. Details of potential environmental determinants of vitamin D status and COPD symptom control and severity were collected by questionnaire, and blood s les were taken for analysis of serum 25(OH)D concentration and DNA extraction. All participants performed spirometry and underwent measurement of weight and height. Quadriceps muscle strength (QS) was measured in 134 participants, and sputum induction with enumeration of lower airway eosinophil and neutrophil counts was performed for 44 participants. Thirty-seven single nucleotide polymorphisms (SNP) in 11 genes in the vitamin D pathway (DBP, DHCR7, CYP2R1, CYP27B1, CYP24A1, CYP27A1, CYP3A4, LRP2, CUBN, RXRA, and VDR) were typed using Taqman allelic discrimination assays. Linear regression was used to identify environmental and genetic factors independently associated with serum 25(OH)D concentration and to determine whether vitamin D status or genetic factors independently associated with % predicted forced expiratory volume in one second (FEV
Publisher: Springer Science and Business Media LLC
Date: 08-10-2014
Abstract: Both high and low vitamin D statuses have been associated with lower memory function. Apolipoprotein E (APOE) ɛ4 alleles have been associated with reduced memory function, and separately with higher vitamin D concentrations. This report aims to examine if the presence of APOE ɛ4 alleles contributes to the relationship between vitamin D and memory function. A total of 4848 (46% female) participants from the 1958 British birth cohort had information on APOE genotypes and completed memory tests at 50 years, where 4644 also had 25-hydroxyvitamin D (25(OH)D) concentrations measured at 45 years. Both low and high 25(OH)D concentrations were associated with lower memory function after adjustment for number of APOE ɛ4 alleles (P curvature=0.02). There was evidence of interaction between APOE ɛ4 and 25(OH)D, suggesting the association between 25(OH)D concentrations and memory function is different for those with two APOE ɛ4 alleles compared with those with zero or one APOE ɛ4 alleles (recessive model P interaction=0.01). Among participants with two APOE ɛ4 alleles, higher 25(OH)D concentrations were associated with higher memory function, whereas in others, memory scores were slightly lower for in iduals with higher versus lower concentrations. Further studies are required to replicate these findings.
Publisher: Springer Science and Business Media LLC
Date: 31-10-2016
DOI: 10.1038/NG.3698
Publisher: Wiley
Date: 04-03-2004
DOI: 10.1111/J.1471-0528.2004.00089.X
Abstract: In a two-generation study of the nationwide 1958 British cohort and their offspring, we investigated the intergenerational influence of birth order on birthweight. Despite increases in own birthweight by birth order and a positive parent-offspring correlation in birthweights, there was a suggestion that parental birth order was inversely associated with offspring birthweight. This paradoxical finding was due to differential intergenerational birthweight associations, with a weaker association in later-born compared with first-born parents. Our findings suggest that underlying causes of a given birthweight should be taken into account in studies that investigate long term health outcomes.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2012
DOI: 10.1038/NG.2245
Publisher: Springer Science and Business Media LLC
Date: 08-04-2012
DOI: 10.1038/NG.2247
Publisher: Wiley
Date: 17-11-2022
DOI: 10.1002/ACR.24884
Abstract: In this Mendelian randomization (MR) study, the objective was to investigate the causal effect of metabolically different adiposity subtypes on osteoarthritis. We performed 2‐s le MR using summary‐level data for osteoarthritis (10,083 cases and 40,425 controls) from a genome‐wide association using the UK Biobank, and for site‐specific osteoarthritis from the Arthritis Research UK Osteoarthritis Genetics consortium. We used 3 classes of genetic instruments, which all increase body mass index but are associated with different metabolic profiles (unfavorable, neutral, and favorable). Primary analysis was performed using inverse variance weight (IVW), with additional sensitivity analysis from different MR methods. We further applied a nonlinear MR using UK Biobank data to understand the nature of the adiposity–osteoarthritis relationship. Greater metabolically unfavorable and metabolically neutral adiposity were associated with higher odds of osteoarthritis (IVW odds ratio [OR] 1.56 [95% confidence interval (95% CI) 1.31, 1.85] and OR 1.60 [95% CI 1.15, 2.23], respectively). The estimate for the association between metabolically favorable adiposity and osteoarthritis was similar, although with notable imprecision (OR 1.55 [95% CI 0.70, 3.41]). Using site‐specific osteoarthritis, metabolically unfavorable, neutral, and favorable adiposity were all associated with higher odds of knee osteoarthritis (OR 1.44 [95% CI 1.04, 1.98], OR 2.28 [95% CI 1.04, 4.99], and OR 6.80 [95% CI 2.08, 22.19], respectively). We found generally consistent estimates with a wider confidence interval crossing the null from other MR methods. The nonlinear MR analyses suggested a nonlinear relationship between metabolically unfavorable adiposity and osteoarthritis ( P nonlinear = 0.003). Metabolic abnormalities did not explain the association between greater adiposity and the risk of osteoarthritis, which might suggest that the association is largely due to a mechanical effect on the joints.
Publisher: Springer Science and Business Media LLC
Date: 20-05-2019
DOI: 10.1038/S41467-019-10128-W
Abstract: The genomics era has brought useful tools to dissect the genetic architecture of complex traits. Here we propose a multivariate reaction norm model (MRNM) to tackle genotype–covariate (G–C) correlation and interaction problems. We apply MRNM to the UK Biobank data in analysis of body mass index using smoking quantity as a covariate, finding a highly significant G–C correlation, but only weak evidence for G–C interaction. In contrast, G–C interaction estimates are inflated in existing methods. It is also notable that there is significant heterogeneity in the estimated residual variances (i.e., variances not attributable to factors in the model) across different covariate levels, i.e., residual–covariate (R–C) interaction. We also show that the residual variances estimated by standard additive models can be inflated in the presence of G–C and/or R–C interactions. We conclude that it is essential to correctly account for both interaction and correlation in complex trait analyses.
Publisher: Springer Science and Business Media LLC
Date: 27-08-2021
DOI: 10.1038/S41366-021-00942-Y
Abstract: Observational and Mendelian randomization (MR) studies link obesity and cancer, but it remains unclear whether these depend upon related metabolic abnormalities. We used information from 321,472 participants in the UK biobank, including 30,561 cases of obesity-related cancer. We constructed three genetic instruments reflecting higher adiposity together with either "unfavourable" (82 SNPs), "favourable" (24 SNPs) or "neutral" metabolic profile (25 SNPs). We looked at associations with 14 types of cancer, previously suggested to be associated with obesity. All genetic instruments had a strong association with BMI (p < 1 × 10 Higher adiposity associated with a higher risk of non-hormonal cancer but a lower risk of some hormone related cancers. Presence of metabolic abnormalities might aggravate the adverse effects of higher adiposity on cancer. Further studies are warranted to investigate whether interventions on adverse metabolic health may help to alleviate obesity-related cancer risk.
Publisher: American Diabetes Association
Date: 02-2008
DOI: 10.2337/DB07-1122
Abstract: OBJECTIVE—Hypovitaminosis D and reduced IGF-1 are associated, in idually, with metabolic syndrome. Physiological interactions between vitamin D and IGF-1 are reported this is the first study to investigate their combined associations with metabolic syndrome prevalence. RESEARCH DESIGN AND METHODS—Data on 25-hydroxyvitamin D (25(OH)D), IGF-1, and metabolic syndrome abnormalities (abdominal obesity raised A1C, blood pressure, and triglycerides and low HDL cholesterol) were collected from 6,810 British white subjects in the 1958 cohort, surveyed during 2002–2004 (age 45 years). RESULTS—IGF-1 concentrations increased with 25(OH)D up to ∼75–85 nmol/l but not thereafter. Both 25(OH)D and IGF-1 were inversely associated with metabolic syndrome. There was an interaction between 25(OH)D and IGF-1 (P = 0.025) on metabolic syndrome prevalence: IGF-1 was not significantly associated with metabolic syndrome among those with the lowest levels of 25(OH)D (P & 0.09), whereas higher 25(OH)D was associated with metabolic syndrome at all IGF-1 concentrations (P ≤ 0.006). Metabolic syndrome prevalence was lowest for participants with the highest concentrations of both 25(OH)D and IGF-1 (odds ratio for highest vs. lowest third of both 0.26 [95% CI 0.17–0.40], P & 0.0001 adjusted for sex, month, hour, inactivity, alcohol consumption, smoking, and social class). 25(OH)D was associated with the prevalence of high A1C, blood pressure, and triglycerides after adjustment for IGF-1, obesity, and social and lifestyle variations (P ≤ 0.004 for all comparisons). CONCLUSIONS—Serum 25(OH)D is inversely associated with metabolic syndrome, whereas the inverse association with IGF-1 was found only among those without hypovitaminosis D. These results suggest that metabolic syndrome prevalence is the lowest when both 25(OH)D and IGF-1 are high.
Publisher: Springer Science and Business Media LLC
Date: 27-07-2021
DOI: 10.1186/S12937-021-00725-1
Abstract: Multiple observational studies have reported an inverse relationship between 25-hydroxyvitamin D concentrations (25(OH)D) and type 2 diabetes (T2D). However, the results of short- and long-term interventional trials concerning the relationship between 25(OH)D and T2D risk have been inconsistent. To evaluate the causal role of reduced blood 25(OH)D in T2D, here we have performed a bidirectional Mendelian randomization study using 59,890 in iduals (5,862 T2D cases and 54,028 controls) from European and Asian Indian ancestries. We used six known SNPs, including three T2D SNPs and three vitamin D pathway SNPs, as a genetic instrument to evaluate the causality and direction of the association between T2D and circulating 25(OH)D concentration. Results of the combined meta-analysis of eight participating studies showed that a composite score of three T2D SNPs would significantly increase T2D risk by an odds ratio (OR) of 1.24, p = 1.82 × 10 –32 Z score 11.86, which, however, had no significant association with 25(OH)D status (Beta -0.02nmol/L ± SE 0.01nmol/L p = 0.83 Z score -0.21). Likewise, the genetically instrumented composite score of 25(OH)D lowering alleles significantly decreased 25(OH)D concentrations (-2.1nmol/L ± SE 0.1nmol/L, p = 7.92 × 10 –78 Z score -18.68) but was not associated with increased risk for T2D (OR 1.00, p = 0.12 Z score 1.54). However, using 25(OH)D synthesis SNP (DHCR7 rs12785878) as an in idual genetic instrument, a per allele reduction of 25(OH)D concentration (-4.2nmol/L ± SE 0.3nmol/L) was predicted to increase T2D risk by 5%, p = 0.004 Z score 2.84. This effect, however, was not seen in other 25(OH)D SNPs (GC rs2282679, CYP2R1 rs12794714) when used as an in idual instrument. Our new data on this bidirectional Mendelian randomization study suggests that genetically instrumented T2D risk does not cause changes in 25(OH)D levels. However, genetically regulated 25(OH)D deficiency due to vitamin D synthesis gene (DHCR7) may influence the risk of T2D.
Publisher: Springer Science and Business Media LLC
Date: 23-07-2014
DOI: 10.1038/NATURE13545
Publisher: Public Library of Science (PLoS)
Date: 14-04-2016
Publisher: BMJ
Date: 12-08-2008
Abstract: Identified aetiological factors for chronic widespread pain (CWP) are largely related to emotional and behavioural factors, but current management leads to modest improvement in symptoms. Vitamin D deficiency has been suggested as a new modifiable risk factor for CWP. To examine the association between vitamin D status (measured by 25-hydroxyvitamin D (25(OH)D)) and CWP in a nationwide population s le of white British adults, accounting for potential mediating and confounding lifestyle factors. 9377 participants born 1 week in March 1958, in England, Scotland or Wales and completing a biomedical assessment at age 45 6824 eligible participants had data on 25(OH)D and completed pain manikins. Prevalence of CWP varied by 25(OH)D concentration in women but not in men, with the lowest prevalence observed for women with 75-99 nmol/l (14.4% for or =100 nmol/l). There was an interaction between 25(OH)D concentration and gender in relation to CWP (interaction, p = 0.006), which was not fully explained by differences in lifestyle or social factors (adjusted interaction, p = 0.03). For women, the association between 25(OH)D concentration and CWP persisted after full adjustment (odds ratio (OR) for <75 nmol/l vs 75-99 nmol/l 1.57, 95% CI 1.09 to 2.26), while no evidence for an association was apparent in men (OR = 1.03, 95% CI 0.75 to 1.43). Current vitamin D status was associated with CWP in women but not in men. Follow-up studies are needed to evaluate whether higher vitamin D intake might have beneficial effects on the risk of CWP.
Publisher: Springer Science and Business Media LLC
Date: 29-10-2019
DOI: 10.1186/S12872-019-1187-Z
Abstract: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Published and in idual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57 1.22) for the GS, compared to 0.85 (95% CI 0.78 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11 1.50) for the GS, as compared to 1.00 (95% CI 0.96 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown although precision was moderate.
Publisher: Springer Science and Business Media LLC
Date: 17-01-2018
DOI: 10.1038/S41467-017-02662-2
Abstract: Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci ( GC, NADSYN1/DHCR7, CYP2R1, CYP24A1 ). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery s le size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants ( P = 4.7×10 −9 at rs8018720 in SEC23A , and P = 1.9×10 −14 at rs10745742 in AMDHD1 ). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
Publisher: Oxford University Press (OUP)
Date: 26-11-2012
Publisher: Public Library of Science (PLoS)
Date: 06-2015
Publisher: Springer Science and Business Media LLC
Date: 02-12-2012
DOI: 10.1038/NG.2477
Publisher: Research Square Platform LLC
Date: 14-10-2021
DOI: 10.21203/RS.3.RS-926833/V1
Abstract: Hormone-related cancers, including cancers of the breast, prostate, ovaries, uterine, and thyroid, globally contribute to the majority of cancer incidence. We hypothesize that hormone-sensitive cancers share common genetic risk factors that have rarely been investigated by previous genomic studies of site-specific cancers. To test this hypothesis, we analysed five hormone-sensitive cancers in the UK Biobank as a single disease. We observed that a significant proportion of variance in disease liability was explained by the genome-wide single nucleotide polymorphisms (SNPs), i.e., SNP-based heritability on the liability scale was estimated as 10.06% (SE 0.70%) for the disease. Moreover, we found 55 genome-wide significant SNPs for the disease, using a genome-wide association study. Our finding suggests that heritable genetic factors may be a key driver in the mechanism of carcinogenesis shared by hormone-sensitive cancers.
Publisher: Oxford University Press (OUP)
Date: 07-2005
DOI: 10.1301/NR.2005.JUL.225-232
Abstract: Preecl sia has been suggested to result from a partial breakdown of tolerance to the developing fetus after maternal immune maladaptation. Several of the proposed immunomodulatory properties of the hormonal vitamin D system could potentially have beneficial effects for successful maintenance of pregnancy. Preecl sia is characterized by marked changes in vitamin D metabolism. This paper reviews the evidence suggesting that the immunomodulatory properties of 1,25(OH)2D may play a key role in maintaining immunological tolerance in pregnancy, and proposes that ensuring adequate vitamin D status/intake may help in the prevention and management of preecl sia.
Publisher: Elsevier BV
Date: 06-2012
Publisher: Elsevier BV
Date: 10-2010
Abstract: Parent-offspring associations in adiposity are well known, but the extent to which they are explained by modifiable environmental and lifestyle factors remains to be elucidated. The objectives were to assess whether 1) parent-offspring associations in body mass index (BMI in kg/m(2)) persist from childhood to midadulthood, 2) parental BMI is associated with the offspring's adult lifestyle, and 3) parent-offspring BMI associations in midadulthood are explained by lifestyle factors. Participants in the 1958 British Birth Cohort Study and their parents (n = 9346) were examined. Parental BMI was assessed in 1969 offspring (ie, cohort members) BMI was ascertained prospectively at 11 and 44-45 y. Lifestyle factors of the offspring, including diet, physical activity, alcohol consumption, and smoking, were assessed prospectively in adulthood. Maternal and paternal BMI were positively associated with offspring BMI in both childhood and midadulthood, and the strength of the association did not diminish with offspring age. Maternal BMI was associated with several offspring lifestyle factors across adulthood fewer associations were observed for paternal BMI. Parent-offspring BMI associations in adulthood were largely maintained after adjustment for multiple lifestyle and socioeconomic factors at different life stages: if parental BMI was 1 unit higher, offspring BMI at 44-45 y was higher by between 0.21 and 0.29 units in adjusted models. Strong parent-offspring BMI associations are maintained into midlife. These associations are largely unaffected by adjustment for a wide range of lifestyle factors. Offspring of obese parents are an important target for interventions aimed at reducing population levels of overweight and obesity.
Publisher: Elsevier BV
Date: 04-2016
Publisher: Springer Science and Business Media LLC
Date: 29-11-2016
DOI: 10.1038/NG1216-1587B
Publisher: Public Library of Science (PLoS)
Date: 12-10-2020
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.ATHEROSCLEROSIS.2013.02.006
Abstract: Circulating levels of 25-hydroxyvitamin D (25OHD) are positively associated with high density lipoprotein (HDL) cholesterol. We sought to replicate a previously reported interaction between APOA5 genotype and vitamin D, and to examine whether HDL-associated genetic loci modify the association between serum 25OHD and HDL cholesterol. We examined whether 42 single nucleotide polymorphisms (SNPs) modify the association between serum 25OHD and HDL cholesterol in the 1958 British Birth cohort (aged 45 years, n = 4978). We identified a borderline interaction between the SNP rs12272004 (near the APOA5) and serum 25OHD on HDL cholesterol (P(interaction) = 0.05). The interaction was particularly prominent among the s les collected during winter (P(interaction) = 0.001). None of the other loci showed an interaction with serum 25OHD concentrations on HDL cholesterol. Our study in 4978 British Whites provides further support that APOA5 genotype modifies the association between vitamin D metabolites and HDL cholesterol.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.JSBMB.2016.11.004
Abstract: Vitamin D deficiency is common in children with asthma, and it associates with poor asthma control, reduced forced expiratory volume in one second (FEV
Publisher: Oxford University Press (OUP)
Date: 07-2005
Publisher: Elsevier BV
Date: 06-2007
DOI: 10.1086/518517
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2015
DOI: 10.1161/CIRCGENETICS.115.001225
Abstract: Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood. Data on 141 317 participants (62 666 never, 40 669 former, 37 982 current smokers) from 23 population-based studies were included in observational and Mendelian randomization meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure, hypertension, and resting heart rate. For the Mendelian randomization analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower systolic blood pressure and diastolic blood pressure and lower hypertension risk, but with higher resting heart rate. In observational analyses among current smokers, 1 cigarette/day higher level of smoking heaviness was associated with higher (0.21 bpm 95% confidence interval 0.19 0.24) resting heart rate and slightly higher diastolic blood pressure (0.05 mm Hg 95% confidence interval 0.02 0.08) and systolic blood pressure (0.08 mm Hg 95% confidence interval 0.03 0.13). However, in Mendelian randomization analyses among current smokers, although each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 bpm/allele 95% confidence interval 0.18 0.54), there was no strong association with diastolic blood pressure, systolic blood pressure, or hypertension. This would suggest a 7 bpm higher heart rate in those who smoke 20 cigarettes/day. This Mendelian randomization meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.
Publisher: Elsevier BV
Date: 06-2021
DOI: 10.1016/J.CLNU.2020.12.042
Abstract: There is evidence that long-term heavy coffee consumption may adversely affect in iduals' cardiovascular disease (CVD) risk. As hyperlipidemia is a well-established contributor to CVD risk, we investigated the association between habitual coffee intake and plasma lipid profile. We used data from up to 362,571 UK Biobank participants to examine phenotypic associations between self-reported coffee intake and plasma lipid profiles, including low-density-lipoproteins cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (total-C), triglycerides, and apolipoproteins A1 and B (ApoA1 and ApoB). Mendelian randomization (MR) analysis using genetically instrumented coffee intake was used to interrogate the causal nature of coffee-lipid associations. We observed a positive dose-dependent association between self-reported coffee intake and plasma concentration of LDL-C, ApoB and total-C, with the highest lipid levels seen among participants reported drinking >6 cups/day (P Our phenotypic and genetic analyses suggest that long-term heavy coffee consumption may lead to unfavourable lipid profile, which could potentially increase in iduals' risk for CVD. These findings may have clinical relevance for people with elevated LDL cholesterol.
Publisher: Springer Science and Business Media LLC
Date: 18-04-2016
DOI: 10.1038/NG.3552
Publisher: Oxford University Press (OUP)
Date: 15-05-2015
DOI: 10.1093/IJE/DYV074
Publisher: American Medical Association (AMA)
Date: 20-09-2019
Publisher: Springer Science and Business Media LLC
Date: 12-10-2022
DOI: 10.1038/S41586-022-05275-Y
Abstract: Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge s le sizes 1 . Here, using data from a genome-wide association study of 5.4 million in iduals of erse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-s le estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel 2 ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller s le sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.
Publisher: Springer Science and Business Media LLC
Date: 11-05-2016
DOI: 10.1038/NATURE17671
Publisher: Informa UK Limited
Date: 24-06-2022
Publisher: Oxford University Press (OUP)
Date: 12-2015
DOI: 10.1530/EJE-15-0839
Abstract: Given the role of uncoupling protein 2 (UCP2) in the accumulation of fat in the hepatocytes and in the enhancement of protective mechanisms in acute ethanol intake, we hypothesised that UCP2 polymorphisms are likely to cause liver disease through their interactions with obesity and alcohol intake. To test this hypothesis, we investigated the interaction between tagging polymorphisms in the UCP2 gene (rs2306819, rs599277 and rs659366), alcohol intake and obesity traits such as BMI and waist circumference (WC) on alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) in a large meta-analysis of data sets from three populations ( n =20 242). The study populations included the Northern Finland Birth Cohort 1966 ( n =4996), Netherlands Study of Depression and Anxiety ( n =1883) and LifeLines Cohort Study ( n =13 363). Interactions between the polymorphisms and obesity and alcohol intake on dichotomised ALT and GGT levels were assessed using logistic regression and the likelihood ratio test. In the meta-analysis of the three cohorts, none of the three UCP2 polymorphisms were associated with GGT or ALT levels. There was no evidence for interaction between the polymorphisms and alcohol intake on GGT and ALT levels. In contrast, the association of WC and BMI with GGT levels varied by rs659366 genotype ( P interaction =0.03 and 0.007, respectively adjusted for age, gender, high alcohol intake, diabetes, hypertension and serum lipid concentrations). In conclusion, our findings in 20 242 in iduals suggest that UCP2 gene polymorphisms may cause liver dysfunction through the interaction with body fat rather than alcohol intake.
Publisher: American Medical Association (AMA)
Date: 06-08-2019
Publisher: Springer Science and Business Media LLC
Date: 2013
Publisher: Cambridge University Press (CUP)
Date: 27-10-2015
DOI: 10.1017/S2040174415007849
Abstract: Fortification of margarine with vitamin D was mandatory in Denmark during 1961–1985. The aim of the study was to assess whether gestational and early infancy exposure to margarine fortification was associated with seasonality of birth in Danish type 1 diabetes (T1D) patients. The risks of T1D in Danes born during various exposure periods around margarine fortification termination in 1985 were analyzed. As expected, the T1D hazards in males unexposed to margarine fortification and born in spring were higher than in males born in autumn: relevant hazard ratios (95% confidence intervals) in various exposure groups ranged from 1.74 (1.112/2.708) to 37.43 (1.804/776.558). There were no indications of seasonality of birth in males exposed to fortification, nor in both exposed and unexposed females. The study suggests that early life exposure to low-dose vitamin D from fortified food eliminates seasonality of birth in T1D male patients. Further studies are required to investigate the identified gender differences.
Publisher: MDPI AG
Date: 26-11-2021
DOI: 10.3390/NU13124260
Abstract: Several observational studies have examined vitamin D pathway polymorphisms and their association with type 1 diabetes (T1D) susceptibility, with inconclusive results. We aimed to perform a systematic review and meta-analysis assessing associations between selected variants affecting 25-hydroxyvitamin D [25(OH)D] and T1D risk. We conducted a systematic search of Medline, Embase, Web of Science and OpenGWAS updated in April 2021. The following keywords “vitamin D” and/or “single nucleotide polymorphisms (SNPs)” and “T1D” were selected to identify relevant articles. Seven SNPs (or their proxies) in six genes were analysed: CYP2R1 rs10741657, CYP2R1 (low frequency) rs117913124, DHCR7/NADSYN1 rs12785878, GC rs3755967, CYP24A1 rs17216707, AMDHD1 rs10745742 and SEC23A rs8018720. Seven case-control and three cohort studies were eligible for quantitative synthesis (n = 10). Meta-analysis results suggested no association with T1D (range of pooled ORs for all SNPs: 0.97–1.02 p 0.01). Heterogeneity was found in DHCR7/NADSYN1 rs12785878 (I2: 64.8%, p = 0.02). Sensitivity analysis showed exclusion of any single study did not alter the overall pooled effect. No association with T1D was observed among a Caucasian subgroup. In conclusion, the evidence from the meta-analysis indicates a null association between selected variants affecting serum 25(OH)D concentrations and T1D.
Publisher: Wiley
Date: 12-03-2009
DOI: 10.1111/J.1398-9995.2008.01865.X
Abstract: Hormonal vitamin D system affects the determination of T-cell responses. It is unknown if there is an association between vitamin D status and allergic conditions. Our aim was to investigate differences in serum IgE concentrations by vitamin D status [measured by 25(OH)D] and by a genetic variation in a key vitamin D activation enzyme (CYP27B1) previously shown to be associated with type 1 diabetes. 9377 participants in the 1958 British birth cohort completed a biomedical assessment at 45 years of age 7288 eligible participants had data on 25(OH)D and IgE, with 6429 having further information on CYP27B1 genotype ()1260C>A). There was a nonlinear association between 25(OH)D and IgE (P-value for curvature = 0.0001). Compared with the reference group with the lowest IgE concentrations [25(OH)D 100-125 nmol/l], IgE concentrations were 29% higher (95% CI 9-48%) for participants with the 25(OH)D 135 nmol/l (adjusted for sex, month, smoking, alcohol consumption, time spent outside, geographical location, social class, PC/TV time, physical activity, body mass index and waist circumference). CYP27B1 genotype was associated with both 25(OH)D (difference for A vs. C allele: 1.88%, 95% CI 0.37-3.4%, P = 0.01) and IgE concentrations ()6.59%, )11.6% to )1.42%, P = 0.01). These data suggest that there may be a threshold effect with both low and high 25(OH)D levels associated with elevated IgE concentrations. The same CYP27B1 allele that is protective of diabetes was associated with increased IgE concentrations.
Publisher: American Diabetes Association
Date: 10-2006
DOI: 10.2337/DC06-0946
Abstract: OBJECTIVE—Obesity is a well-known risk factor for vitamin D deficiency. We evaluated the interrelationship between vitamin D status, body size, and glucose homeostasis, measured by HbA1c (A1C). RESEARCH DESIGN AND METHODS—Data are from the survey of the 45-year-old 1958 British birth cohort (2002–2004). Information on A1C, 25-hydroxyvitamin D [25(OH)D an indicator of vitamin D status], and BMI was collected from 7,198 Caucasian subjects. RESULTS—25(OH)D was & nmol/l in 80% of the obese subjects (BMI ≥30 kg/m2) versus 68% of the other subjects (P & 0.0001). Serum 25(OH)D decreased and A1C increased by increasing BMI (P & 0.0001 for both comparisons). There was a nonlinear association between 25(OH)D and A1C: a steep linear decrease in A1C by 25(OH)D until 65 nmol/l and only smaller decreases with further increases. There was evidence for effect modification by BMI in the association between 25(OH)D and A1C (P & 0.0001), and differences appeared stronger for participants with higher compared with lower BMIs. After adjustment for sex, season, geographical location, physical activity, and social class, percent change in A1C by 10-nmol/l increase in 25(OH)D was −0.21 (95% CI −0.31 to −0.11) for BMI & kg/m2, −0.25 (−0.37 to −0.13) for BMI 25–29.9 kg/m2, −0.65 (−0.95 to −0.34) for BMI 30–34.9 kg/m2, and −1.37 (−2.09 to −0.64) for BMI ≥35 kg/m2. CONCLUSIONS—Body size was a strong determinant for 25(OH)D, with concentrations being suboptimal in most obese participants. Randomized controlled trials [using dosages sufficient to improve 25(OH)D also for the obese] are required to determine whether clinically relevant improvements in glucose metabolism can be obtained by vitamin D supplementation.
Publisher: Elsevier BV
Date: 05-2013
Publisher: Elsevier BV
Date: 07-2021
DOI: 10.1093/AJCN/NQAB014
Abstract: Excessive coffee consumption can lead to unpleasant sensations such as tachycardia and heart palpitations. Our aim was to investigate if cardiovascular symptoms can lead to alterations in habitual patterns of coffee consumption. We used information from up to 390,435 European ancestry participants in the UK Biobank, aged 39-73 y. Habitual coffee consumption was self-reported, and systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate were measured at baseline. Cardiovascular symptoms at baseline were based on hospital diagnoses, primary care records, and/or self-report. Mendelian randomization (MR) was used to examine genetic evidence for a causal association between SBP, DBP, and heart rate with habitual coffee consumption. Participants with essential hypertension, angina, or heart arrhythmia were all more likely to drink less caffeinated coffee and to be non-habitual or decaffeinated coffee drinkers compared with those who did not report related symptoms (P ≤ 3.5 × 10-8 for all comparisons). Higher SBP and DBP were associated with lower caffeinated coffee consumption at baseline, with consistent genetic evidence to support a causal explanation across all methods [MR-Egger regression (MREggr) β: -0.21 cups/d (95% CI: -0.34, -0.07) per 10 mm Hg higher SBP and -0.33 (-0.61, -0.07) per 10 mm Hg higher DBP)]. In genetic analyses, higher resting heart rate was associated with a greater odds of being a decaffeinated coffee drinker (MREggr OR: 1.71 95% CI: 1.31, 2.21) per 10 beats/min). We provide causal genetic evidence for cardiovascular system-driven influences on habitual coffee intakes, suggesting that people tend to naturally regulate their coffee consumption based on blood pressure levels and heart rate. These findings suggest that observational studies of habitual coffee intakes are prone to influences by reverse causation, and caution is required when inferred health benefits result from comparisons with coffee abstainers or decaffeinated coffee drinkers.
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1093/AJCN/NQAC107
Publisher: Cambridge University Press (CUP)
Date: 04-06-2010
DOI: 10.1017/S0007114510002175
Abstract: The aim of the present study was to examine the association between maternal Hb levels during pregnancy and educational achievement of the offspring in later life. We analysed data obtained from the Northern Finnish Birth Cohort Study conducted in 1966, in which, data on mothers and offspring from pregnancy through to the age of 31 years were collected. The cohort comprised 11 656 in iduals born from singleton births (51 % males and 49 % females). Maternal Hb levels were available from the third, seventh and ninth gestational months. Educational achievement was measured as school scores (range 4–10) taken at the ages of 14 (self-reported questionnaires) and 16 (school reports) years as well as the highest level of education at the age of 31 years. The present results showed a direct positive association between Hb levels and educational achievement in later life. After adjustment for sex, birth weight, birth month and a wide range of maternal factors (parity, smoking, mental status, whether pregnancy was wanted or not, education, social class and marital status), only maternal Hb levels that were measured at the ninth month were significantly associated with the offspring's school performance. If the levels were ≥ 110 g/l at all the three measurement points, offspring not only had better school scores at the ages of 14 and 16 years (β = 0·048, P = 0·04 and β = 0·68, P = 0·007, respectively), but also had an increased odds of having a higher level of education at the age of 31 years (OR = 1·14, P = 0·04). The present study suggests that low maternal Hb levels at the final stages of pregnancy are linked to the poorer educational achievement of the offspring. If our observation is confirmed, it would suggest that Fe prophylaxis even at fairly late stages of pregnancy may be beneficial for the subsequent health of the offspring. However, more studies are needed to fully establish the potential pathways and the clinical importance of the present findings.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-03-2016
Abstract: Coronary heart disease is a tale of two forms of plasma cholesterol. In contrast to the well-established effects of “bad” cholesterol (LDL-C), the role of “good” cholesterol (HDL-C) is mysterious. Elevated HDL-C correlates with a lower risk of heart disease, yet drugs that raise HDL-C levels do not reduce risk. Zanoni et al. found that some people with exceptionally high levels of HDL-C carry a rare sequence variant in the gene encoding the major HDL-C receptor, scavenger receptor BI. This variant destroys the receptor's ability to take up HDL-C. Interestingly, people with this variant have a higher risk of heart disease despite having high levels of HDL-C. Science , this issue p. 1166
Publisher: Springer Science and Business Media LLC
Date: 11-05-2015
DOI: 10.1038/NG.3300
Publisher: Public Library of Science (PLoS)
Date: 20-06-2019
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14177
Publisher: Springer Science and Business Media LLC
Date: 19-08-2020
DOI: 10.1038/S41380-019-0486-1
Abstract: Depression affects all aspects of an in idual's life but evidence relating to the causal effects on health is limited. We used information from 337,536 UK Biobank participants and performed hypothesis-free phenome-wide association analyses between major depressive disorder (MDD) genetic risk score (GRS) and 925 disease outcomes. GRS-disease outcome associations passing the multiple-testing corrected significance threshold (P < 1.9 × 10
Publisher: Oxford University Press (OUP)
Date: 17-05-2023
DOI: 10.1093/IJE/DYAC087
Abstract: Low vitamin D status is often associated with systemic low-grade inflammation as reflected by elevated C-reactive protein (CRP) levels. We investigated the causality and direction of the association between vitamin D status and CRP using linear and non-linear Mendelian randomization (MR) analyses. MR analyses were conducted using data from 294 970 unrelated participants of White-British ancestry from the UK Biobank. Serum 25-hydroxyvitamin D [25(OH)D] and CRP concentrations were instrumented using 35 and 46 genome-wide significant variants, respectively. In non-linear MR analysis, genetically predicted serum 25(OH)D had an L-shaped association with serum CRP, where CRP levels decreased sharply with increasing 25(OH)D concentration for participants within the deficiency range (& nmol/L) and levelled off at ∼50 nmol/L of 25(OH)D (Pnon-linear = 1.49E-4). Analyses using several pleiotropy-robust methods provided consistent results in stratified MR analyses, confirming the inverse association between 25(OH)D and CRP in the deficiency range (P = 1.10E-05) but not with higher concentrations. Neither linear or non-linear MR analysis supported a causal effect of serum CRP level on 25(OH)D concentration (Plinear = 0.32 and Pnon-linear = 0.76). The observed association between 25(OH)D and CRP is likely to be caused by vitamin D deficiency. Correction of low vitamin D status may reduce chronic inflammation.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/C9QI01262A
Abstract: A Zn-MOF was constructed by a F-decorated ligand and bipyridyl linkers, displaying selective adsorption for CO 2 , C 2 H 6 , C 2 H 2 over CH 4 , catalysis for CO 2 conversion and selective adsorption for methyl blue.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2013
DOI: 10.1038/IJO.2013.6
Publisher: Elsevier BV
Date: 08-2017
Publisher: Springer Science and Business Media LLC
Date: 23-07-2018
Publisher: Wiley
Date: 14-02-2007
DOI: 10.1111/J.1464-5491.2006.02055.X
Abstract: Information on the population at risk of developing Type 2 diabetes in the UK is scarce. We used data from the 1958 British birth cohort to estimate geographical and socio-economic variations in HbA(1c) in mid life. Participants (n = 7799) born in England, Scotland and Wales and currently living in the UK. In iduals were classified according to the presence of Type 2 diabetes and by thresholds of HbA(1c). HbA(1c)> or = 5.5 was used as an indicator for possible subclinical alterations in glucose metabolism. The majority of the population had HbA(1c) or = 7.0%. In iduals from manual socio-economic groups and those living in the East of England and Scotland had a higher prevalence of HbA(1c) at or above the upper normal range (5.5%). Estimates from this nationwide s le suggest that a proportion of Britons are likely to have subclinical alterations in glucose metabolism by their mid 40s, and this proportion is greater in some socio-economic groups and geographical regions than in others.
Publisher: Springer Science and Business Media LLC
Date: 14-08-2018
Publisher: American Public Health Association
Date: 08-2005
Abstract: Objectives. We sought to establish whether women’s childhood socioeconomic position influenced their risk of mortality separately from the effects of adult socioeconomic position. Methods. We examined 11855 British women aged 14 to 49 years, with mortality follow-up over a 45-year period. Results. Trends according to childhood social class were observed for all-cause mortality, circulatory disease, coronary heart disease, respiratory disease, chronic obstructive pulmonary disease, stroke, lung cancer, and stomach cancer, with higher death rates among members of unskilled manual groups. Associations attenuated after adjustment for adult social class, smoking, and body mass index. No trend was seen for breast cancer or accidents and violence. Adverse social conditions in both childhood and adulthood were associated with higher death rates from coronary heart disease and respiratory disease. Stomach cancer was influenced primarily by childhood conditions and lung cancer by factors in adult life. Conclusions. Socioeconomic position in childhood was associated with adult mortality in a large s le of British women.
Publisher: Public Library of Science (PLoS)
Date: 09-06-2016
Publisher: Cambridge University Press (CUP)
Date: 06-06-2011
DOI: 10.1017/S0007114511001991
Abstract: Higher vitamin D concentrations have been proposed as a protective ‘seasonal stimulus’ against influenza, and there are suggestions for associations with other aspects of respiratory health. The aim of the present study was to investigate the relationship of current vitamin D status (measured by 25-hydroxyvitamin D, 25(OH)D) with respiratory infections and lung function. We used cross-sectional data from 6789 participants in the nationwide 1958 British birth cohort who had measurements of 25(OH)D, lung function (forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC)) and respiratory infections available from the age of 45 years. In this population, the prevalence of respiratory infections had a strong seasonal pattern in the opposite direction to the pattern for 25(OH)D concentrations. Each 10 nmol/l increase in 25(OH)D was associated with a 7 % lower risk of infection (95 % CI 3, 11 %) after adjustment for adiposity, lifestyle and socio-economic factors. For FEV 1 and FVC, each 10 nmol/l increase in 25(OH)D was associated with 8 (95 % CI 3, 13) ml and 13 (95 % CI 7, 20) ml higher volume, respectively, after controlling for covariates. Associations of 25(OH)D with FEV 1 and FVC were only slightly attenuated after further adjustment for infection and other respiratory illness. In conclusion, vitamin D status had a linear relationship with respiratory infections and lung function. Randomised controlled trials are warranted to investigate the role of vitamin D supplementation on respiratory health and to establish the underlying mechanisms.
Publisher: Springer Science and Business Media LLC
Date: 05-10-2014
DOI: 10.1038/NG.3097
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.DIABET.2014.01.003
Abstract: 25-hydroxyvitamin D (25OHD) concentrations have been shown to be associated with major clinical outcomes, with a suggestion that in idual risk may vary according to common genetic differences in the vitamin D receptor (VDR) gene. Hence, we tested for the interactions between two previously studied VDR polymorphisms and 25OHD on metabolic and cardiovascular disease-related outcomes in a large population-based study. Interactions between two previously studied VDR polymorphisms (rs7968585 and rs2239179) and 25OHD concentrations on metabolic and cardiovascular disease-related outcomes such as obesity- (body mass index, waist circumference, waist-hip ratio (WHR)), cardiovascular- (systolic and diastolic blood pressure), lipid- (high- and low-density lipoprotein, triglycerides, total cholesterol), inflammatory- (C-reactive protein, fibrinogen, insulin growth factor-1, tissue plasminogen activator) and diabetes- (glycated haemoglobin) related markers were examined in the 1958 British Birth cohort (n up to 5160). Interactions between each SNP and 25OHD concentrations were assessed using linear regression and the likelihood ratio test. After Bonferroni correction, none of the interactions reached statistical significance except for the interaction between the VDR SNP rs2239179 and 25OHD concentrations on waist-hip ratio (WHR) (P=0.03). For every 1nmol/L higher 25OHD concentrations, the association with WHR was stronger among those with two major alleles (-4.0%, P=6.26e(-24)) compared to those with either one or no major alleles (-2.3%, P≤8.201e(-07), for both) of the VDR SNP rs2239179. We found no evidence for VDR polymorphisms acting as major modifiers of the association between 25OHD concentrations and cardio-metabolic risk. Interaction between VDR SNP rs2239179 and 25OHD on WHR warrants further confirmation.
Publisher: Cambridge University Press (CUP)
Date: 2015
Publisher: Hindawi Limited
Date: 14-10-2019
DOI: 10.1002/DA.22963
Abstract: This study aimed to explore the association between depression and body mass index (BMI), and to investigate whether genetic susceptibility to high BMI is different among in iduals with or without depression. We used data on 251,125 in iduals of white British ancestry from the UK Biobank. We conducted Mendelian randomization (MR) analysis to test for a causal association between depression and BMI using a major depressive disorder (MDD)-related genetic risk score (GRS We found observational and genetic evidence for an association between depression and BMI (MR beta: 0.09, 95% confidence interval [CI] 0.04-0.13). Further, the contribution of genetic risk to high BMI was higher among in iduals with depression compared to controls. Carrying 10 additional BMI increasing alleles was associated with 0.24 standard deviation (SD 95%CI 0.23-0.25) higher BMI among depressed in iduals compared to 0.20 SD (95%CI 0.19-0.21) higher in controls, which corresponds to 3.4 kg and 2.8 kg extra weight for an in idual of average height. Amongst the in idual loci, the evidence for interaction was most notable for a variant near MC4R, a gene known to affect both appetite regulation and the hypothalamic-pituitary adrenal axis (p Genetic predisposition to high BMI was higher among depressed than to nondepressed in iduals. This study provides support for a possible role of MC4R in the link between depression and obesity.
Publisher: Springer Science and Business Media LLC
Date: 08-09-2004
Publisher: Elsevier BV
Date: 2004
Publisher: Elsevier BV
Date: 11-2001
Publisher: Springer Science and Business Media LLC
Date: 26-11-2021
DOI: 10.1038/S41598-021-02476-9
Abstract: We present a simple and efficient hypothesis-free machine learning pipeline for risk factor discovery that accounts for non-linearity and interaction in large biomedical databases with minimal variable pre-processing. In this study, mortality models were built using gradient boosting decision trees (GBDT) and important predictors were identified using a Shapley values-based feature attribution method, SHAP values. Cox models controlled for false discovery rate were used for confounder adjustment, interpretability, and further validation. The pipeline was tested using information from 502,506 UK Biobank participants, aged 37–73 years at recruitment and followed over seven years for mortality registrations. From the 11,639 predictors included in GBDT, 193 potential risk factors had SHAP values ≥ 0.05, passed the correlation test, and were selected for further modelling. Of the total variable importance summed up, 60% was directly health related, and baseline characteristics, sociodemographics, and lifestyle factors each contributed about 10%. Cox models adjusted for baseline characteristics, showed evidence for an association with mortality for 166 out of the 193 predictors. These included mostly well-known risk factors (e.g., age, sex, ethnicity, education, material deprivation, smoking, physical activity, self-rated health, BMI, and many disease outcomes). For 19 predictors we saw evidence for an association in the unadjusted but not adjusted analyses, suggesting bias by confounding. Our GBDT-SHAP pipeline was able to identify relevant predictors ‘hidden’ within thousands of variables, providing an efficient and pragmatic solution for the first stage of hypothesis free risk factor identification.
Publisher: Cambridge University Press (CUP)
Date: 18-10-2013
DOI: 10.1017/S0007114513003176
Abstract: Hypovitaminosis D has been linked with poor cognitive function, particularly in older adults, but studies lack a lifespan approach hence, the effects of reverse causality remain unknown. In the present study, we aimed to assess the relationship between 25-hydroxyvitamin D (25(OH)D) concentrations and subsequent cognitive performance in mid-adulthood and the influence of earlier life factors, including childhood cognitive ability, on this association. Information for the present study was obtained from the members of the 1958 British birth cohort ( n 6496). Serum 25(OH)D concentration, indicating vitamin D status, was measured at age 45 years. Verbal memory (immediate and delayed word recall), verbal fluency (animal naming) and speed of processing were tested at age 50 years. Information on childhood cognitive ability, educational attainment, vitamin D-related behaviours and other covariates was collected prospectively from participants throughout their life. Childhood cognitive ability and educational attainment by age 42 years were strongly correlated with cognitive performance at age 50 years and with several vitamin D-related behaviours in mid-adulthood, but not with 25(OH)D concentrations at age 45 years. Participants with both low ( 25 nmol/l) and high ( ≥ 75 nmol/l) 25(OH)D concentrations at age 45 years performed significantly worse on immediate word recall. The associations attenuated after adjustment for childhood cognitive ability, education, and socio-economic position however, for the immediate word recall test, there was a non-linear association with 25(OH)D after further adjustment for obesity, menopausal status, smoking, alcohol consumption, physical activity and depressive symptoms at age 45 years ( P curvature = 0·01). The present study demonstrated that 25(OH)D concentrations were non-linearly associated with immediate word recall in mid-life. A clarification of the level of 25(OH)D concentrations that is most beneficial for predicting better cognitive performance in mid-life is required.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Cambridge University Press (CUP)
Date: 18-04-2016
Publisher: Springer Science and Business Media LLC
Date: 06-10-2013
DOI: 10.1038/NG.2795
Publisher: Springer Science and Business Media LLC
Date: 06-10-2013
DOI: 10.1038/NG.2797
Publisher: American Medical Association (AMA)
Date: 06-2010
Publisher: Wiley
Date: 12-2004
Abstract: Allergen-induced secretion of Th2-type cytokines and IgE production have recently been reported to be increased in mice treated with 1,25(OH)(2)D, the active form of vitamin D. Our objective was to investigate whether vitamin D supplementation in infancy is associated with the risk of atopy, allergic rhinitis, and asthma. The Northern Finland Birth Cohort consists of all in iduals in the two most northern provinces of Finland who were due to be born in 1966. Data on vitamin D supplementation during the first year of life was obtained in 1967. Current asthma and allergic rhinitis were reported at age 31 years (n = 7,648), and atopy determined by skin-prick test in a sub-s le still living in northern Finland or the Helsinki area (n = 5,007). The prevalence of atopy and allergic rhinitis at age 31 years was higher in participants who had received vitamin D supplementation regularly during the first year compared to others (OR 1.46, 95%CI 1.4-2.0, and OR 1.66, 95%CI 1.1-1.6, respectively). A similar association was observed for asthma (OR 1.35, 95%CI 0.99-1.8). These associations persisted after adjustment for a wide range of behavioral and social factors (adjusted: OR 1.33 for all, P = 0.01 for atopy, P = 0.001 for allergic rhinitis, and P = 0.08 for asthma). We observed an association between vitamin D supplementation in infancy and an increased risk of atopy and allergic rhinitis later in life. Further study is required to determine whether these observations reflect long-term effects on immune regulation or differences in unmeasured determinants of vitamin D supplementation.
Publisher: Public Library of Science (PLoS)
Date: 04-12-2014
Publisher: Wiley
Date: 12-06-2012
DOI: 10.1111/J.1398-9995.2012.02856.X
Abstract: The hormonal form of vitamin D affects both adaptive and innate immune functions involved in the development of allergies. Certain genotypes have been seen to alter the association between vitamin D deficiency (VDD) and the risk of food sensitization in children. We examined 27 functional single nucleotide polymorphisms (SNPs) in/near selected candidate genes for association with total immunoglobulin E (IgE) and effect modification by 25-hydroxyvitamin D in the 1958 British birth cohort (aged 45 years, n = 4921). A cut-off value of 50 nmol/L was used to define VDD. Four SNPs (in FCER1A, IL13, and CYP24A1) and three SNPs (in IL4 and CYP24A1) were associated with total IgE and specific IgE, respectively, after correction for multiple testing. As in a previous study, MS4A2 (rs512555, P(interaction) = 0.04) and IL4 (rs2243250, P(interaction) = 0.02), and their composite score (P(interaction) = 0.009) modified the association between VDD and allergy-related outcome. Vitamin D deficiency was associated with higher total IgE only in the carriers of the 'C' allele (IL4), which is present in 86% of white Europeans, while only 26% of Chinese and <20% of some African populations are carriers. Our study on white European adults was consistent with a previous study on children from largely non-white ethnic groups, suggesting that IL4 and MS4A2 genotypes modify the association between VDD and allergy risk. The risk allele in IL4 is present in nearly 90% of white Europeans, while less than a quarter are carriers in some other populations, highlighting the need to consider possible ethnic differences in allergy-related responsiveness to VDD.
Publisher: BMJ
Date: 10-07-2014
DOI: 10.1136/BMJ.G4164
Publisher: Springer Science and Business Media LLC
Date: 22-05-2017
DOI: 10.1038/S41598-017-01977-W
Abstract: Observational studies on smoking and risk of hay fever and asthma have shown inconsistent results. However, observational studies may be biased by confounding and reverse causation. Mendelian randomization uses genetic variants as markers of exposures to examine causal effects. We examined the causal effect of smoking on hay fever and asthma by using the smoking-associated single nucleotide polymorphism (SNP) rs16969968/rs1051730. We included 231,020 participants from 22 population-based studies. Observational analyses showed that current vs never smokers had lower risk of hay fever (odds ratio (OR) = 0·68, 95% confidence interval (CI): 0·61, 0·76 P 0·001) and allergic sensitization (OR = 0·74, 95% CI: 0·64, 0·86 P 0·001), but similar asthma risk (OR = 1·00, 95% CI: 0·91, 1·09 P = 0·967). Mendelian randomization analyses in current smokers showed a slightly lower risk of hay fever (OR = 0·958, 95% CI: 0·920, 0·998 P = 0·041), a lower risk of allergic sensitization (OR = 0·92, 95% CI: 0·84, 1·02 P = 0·117), but higher risk of asthma (OR = 1·06, 95% CI: 1·01, 1·11 P = 0·020) per smoking-increasing allele. Our results suggest that smoking may be causally related to a higher risk of asthma and a slightly lower risk of hay fever. However, the adverse events associated with smoking limit its clinical significance.
Publisher: Cold Spring Harbor Laboratory
Date: 21-07-2023
DOI: 10.1101/2023.07.20.549816
Abstract: The use of polygenic risk score (PRS) models has transformed the field of genetics by enabling the prediction of complex traits and diseases based on an in idual’s genetic profile. However, the impact of genotype-environment interaction (GxE) on the performance and applicability of PRS models remains a crucial aspect to be explored. Currently, existing GxE PRS models are often inappropriately used, which can result in inflated type 1 error rates and compromised results. In this study, we propose a novel GxE PRS model that correctly incorporates the GxE component to analyze complex traits and diseases. Through extensive simulations, we demonstrate that our proposed model outperforms existing models in terms of controlling type 1 error rates and enhancing statistical power. Furthermore, we apply the proposed model to real data, and report significant GxE effects. Specifically, we highlight the impact of our model on both quantitative and binary traits. For quantitative traits, we uncover the GxE modulation of genetic effects on body mass index (BMI) by alcohol intake frequency (ALC). In the case of binary traits, we identify the GxE modulation of genetic effects on hypertension (HYP) by waist-to-hip ratio (WHR). These findings underscore the importance of employing a robust model that effectively controls type 1 error rates, thus preventing the occurrence of spurious GxE signals. To facilitate the implementation of our approach, we have developed an innovative R software package called GxE PRS, specifically designed to detect and estimate GxE effects. Overall, our study highlights the importance of accurate GxE modeling and its implications for genetic risk prediction, while providing a practical tool to support further research in this area.
Publisher: Springer Science and Business Media LLC
Date: 31-01-2007
Abstract: Vitamin D has been suggested to affect the balance between T helper (Th1) and (Th2) type cytokines by favouring Th2 domination. We investigated the association between infant vitamin D supplementation and later pre-ecl sia, a disorder suggested to be dominated by Th1 response. We used data on 2969 women born in the Northern Finland Birth Cohort 1966 of whom 68 (2.3%) had pre-ecl sia in their first pregnancy. Risk of pre-ecl sia was halved (OR 0.49, 95% confidence interval (CI) 0.26-0.92) in participants who had received vitamin D supplementation regularly during the first year of life and this association was not affected by adjustment for own birth order, birth weight, gestational age, social class in 1966 and hospitalizations or pregnancy-induced hypertension of their mothers. Together with earlier observations on a reduced risk of type 1 diabetes after vitamin D supplementation, these data suggest that vitamin D intake in infancy may affect long-term programming of the immune response pattern.
Publisher: BMJ
Date: 20-04-2011
Abstract: To assess the association between working patterns and vitamin D status in men and women and to determine the potential influence of related lifestyle and socioeconomic factors. The authors used data from the 1958 British birth cohort (aged 45 years) and 6154 participants, who were in full-time work, were included in current analyses. Vitamin D status was measured by circulating concentrations of 25-hydroxyvitamin D (25(OH)D). Information on working patterns and lifestyle factors was obtained using a structured questionnaire administered at 45 years. Manual social class was strongly associated with vitamin D-related lifestyle factors, with those in manual classes not only spending more time outdoors, but also spending more time watching TV/using PC, consuming less supplements and oily fish. Associations between working patterns and vitamin D-related lifestyles were less clear: night work was not strongly associated with lifestyles in either gender, while working hours were associated with time spent outside, PC/TV leisure time and use of supplements in men but not in women. In men, working patterns were not associated with lower 25(OH)D concentrations. In women, 25(OH)D concentrations were 8% lower (95% CI 15% to 2%) in night workers compared with others, while women working less than 35 h/week had 5% higher concentrations of 25(OH)D (95% CI 1% to 8%) compared with those working 35-40 h/week after adjustment for season, social class and body mass index (BMI). Women working nights and longer hours may be vulnerable to deficits in vitamin D status and associated health hazards.
Publisher: Elsevier BV
Date: 07-2019
Publisher: Wiley
Date: 13-07-2012
DOI: 10.1096/FJ.12-210880
Abstract: Adipose tissue inflammation is an important pathological process in obese people, associated with diabetes and cardiovascular disease. We hypothesized that 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] inhibits cytokine secretion from adipocytes via direct inhibition of transcription factor nuclear factor-κB (NF-κB). We utilized two different human models. Bone marrow-derived human mesenchymal stromal cells (hMSCs) differentiated into adipocytes, and adipocytes isolated from biopsies stimulated with lipopolysaccharide (LPS) were treated with or without 1,25(OH)(2)D(3). Expression and secretion of interleukin-6 (IL-6) were measured by quantitative RT-PCR analysis and ELISA. Assessment of NF-κB nuclear translocation, DNA binding activity was performed by immunofluorescence (IF) and electrophoretic mobility assay (EMSA). Inhibitor κB (IκB) and its phosphorylation were detected by Western blot (WB) analysis. Simultaneous 1,25(OH)(2)D(3) cotreatment significantly reduced LPS-stimulated (10 ng/ml) IL-6 secretion dose dependently by 15% at 10(-10) M and 26% at 10(-7) M (P<0.05) in hMSCs, while preincubation with 1,25(OH)(2)D(3) (10(-7) M) for 24 h reduced IL-6 secretion by 24 and 35% (P<0.001) and mRNA levels by 34 and 30% (P<0.05) in hMSCs and isolated adipocytes, respectively. 1,25(OH)(2)D(3) suppressed LPS-stimulated IκB phosphorylation-mediated NF-κB translocation into the nucleus were evident from WB, IF, and EMSA. 1,25(OH)(2)D(3) inhibits LPS-stimulated IL-6 secretion in two human adipocyte models via interference with NF-κB signaling.
Publisher: Springer Science and Business Media LLC
Date: 11-04-2010
DOI: 10.1038/NG.566
Publisher: Springer Science and Business Media LLC
Date: 06-04-2010
DOI: 10.1038/NG.567
Publisher: Springer Science and Business Media LLC
Date: 16-10-2017
DOI: 10.1038/S41598-017-13189-3
Abstract: The causal nature of the association between hypovitaminosis D and poor cognitive function in mid- to later-life is uncertain. Using a Mendelian randomisation(MR) approach, we examined the causal relationship between 25(OH)D and cognitive function. Data came from 172,349 participants from 17 cohorts. DHCR7 (rs12785878), CYP2R1 rs12794714) and their combined synthesis score were chosen to proxy 25(OH)D. Cognitive tests were standardised into global and memory scores. Analyses were stratified by 25(OH)D tertiles, sex and age. Random effects meta-analyses assessed associations between 25(OH)D and cognitive function. Associations of serum 25(OH)D with global and memory-related cognitive function were non-linear (lower cognitive scores for both low and high 25(OH)D, p curvature ≤ 0.006), with much of the curvature attributed to a single study. DHCR7 , CYP2R1 , and the synthesis score were associated with small reductions in 25(OH)D per vitamin D-decreasing allele. However, coefficients for associations with global or memory-related cognitive function were non-significant and in opposing directions for DHCR7 and CYP2R1 , with no overall association observed for the synthesis score . Coefficients for the synthesis score and global and memory cognition were similar when stratified by 25(OH)D tertiles, sex and age. We found no evidence for serum 25(OH)D concentration as a causal factor for cognitive performance in mid- to later life.
Publisher: Wiley
Date: 06-06-2023
DOI: 10.1111/BCP.15793
Abstract: Lipid‐lowering medications are widely used to control blood cholesterol levels and manage a range of cardiovascular and lipid disorders. We aimed to explore the possible associations between LDL lowering and multiple disease outcomes or biomarkers. We performed a Mendelian randomization phenome‐wide association study (MR‐PheWAS) in 337 475 UK Biobank participants to test for associations between four proposed LDL‐C‐lowering genetic risk scores ( PCSK9 , HMGCR , NPC1L1 and LDLR ) and 1135 disease outcomes, with follow‐up MR analyses in 52 serum, urine, imaging and clinical biomarkers. We used inverse‐variance weighted MR in the main analyses and complementary MR methods (weighted median, weighted mode, MR‐Egger and MR‐PRESSO) as sensitivity analyses. We accounted for multiple testing with false discovery rate correction ( P 2.0 × 10 −4 for phecodes, P 1.3 × 10 −2 for biomarkers). We found evidence for an association between genetically instrumented LDL lowering and 10 distinct disease outcomes, suggesting potential causality. All genetic instruments were associated with hyperlipidaemias and cardiovascular diseases in the expected directions. Biomarker analyses supported an effect of LDL‐C lowering through PCSK9 on lung function (FEV [beta per 1 mg/dL lower LDL‐C −1.49, 95% CI −2.21, −0.78] FVC [−1.42, 95% CI −2.29, −0.54]) and through HMGCR on hippoc al volume (beta per 1 mg/dL lower LDL‐C 6.09, 95% CI 1.74, 10.44). We found genetic evidence to support both positive and negative effects of LDL‐C lowering through all four LDL‐C‐lowering pathways. Future studies should further explore the effects of LDL‐C lowering on lung function and changes in brain volume.
Publisher: Springer Science and Business Media LLC
Date: 07-05-2020
Publisher: Oxford University Press (OUP)
Date: 05-09-2012
DOI: 10.1093/HMG/DDS372
Publisher: Wiley
Date: 21-09-2023
DOI: 10.1111/DOM.14853
Abstract: To evaluate associations of metabolic profiles and biomarkers with brain atrophy, lesions, and iron deposition to understand the early risk factors associated with dementia. Using data from 26 239 UK Biobank participants free from dementia and stroke, we assessed the associations of metabolic subgroups, derived using an artificial neural network approach (self‐organizing map), and 39 in idual biomarkers with brain MRI measures: total brain volume (TBV), grey matter volume (GMV), white matter volume (WMV), hippoc al volume (HV), white matter hyperintensity (WMH) volume, and caudate iron deposition. In metabolic subgroup analyses, participants characterized by high triglycerides and liver enzymes showed the most adverse brain outcomes compared to the healthy reference subgroup with high‐density lipoprotein cholesterol and low body mass index (BMI) including associations with GMV ( β standardized −0.20, 95% confidence interval [CI] −0.24 to −0.16), HV ( β standardized −0.09, 95% CI −0.13 to −0.04), WMH volume ( β standardized 0.22, 95% CI 0.18 to 0.26), and caudate iron deposition ( β standardized 0.30, 95% CI 0.25 to 0.34), with similar adverse associations for the subgroup with high BMI, C‐reactive protein and cystatin C, and the subgroup with high blood pressure (BP) and apolipoprotein B. Among the biomarkers, striking associations were seen between basal metabolic rate (BMR) and caudate iron deposition ( β standardized 0.23, 95% CI 0.22 to 0.24 per 1 SD increase), GMV ( β standardized −0.15, 95% CI −0.16 to −0.14) and HV ( β standardized −0.11, 95% CI −0.12 to −0.10), and between BP and WMH volume ( β standardized 0.13, 95% CI 0.12 to 0.14 for diastolic BP). Metabolic profiles were associated differentially with brain neuroimaging characteristics. Associations of BMR, BP and other in idual biomarkers may provide insights into actionable mechanisms driving these brain associations.
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.CLNU.2013.01.006
Abstract: The relationship between vitamin D and common mental disorders (CMDs) remains unclear. We aimed to determine if behaviours affecting vitamin D concentrations differ between in iduals with or without CMDs and evaluate, cross-sectionally and prospectively, the extent to which the association between 25(OH)D and CMDs are explained by these behaviours. Data are from the 1958 British birth cohort (n = 7401). Behaviours were ascertained by questionnaire at age 45 years. CMDs (depression, anxiety, panic, phobia) were assessed using the Clinical Interview Schedule-Revised at 45 years and depression using Mental Health Inventory-5 at 50 years. Participants with CMDs at 45 years differed from others on some but not all vitamin D related behaviours. There were inverse, cross-sectional associations at 45 years of 25(OH)D with depression and panic, which persisted after adjustment for vitamin D related behaviours (OR = 0.57, 95% CI: 0.40,0.81 and OR = 0.33, 95% CI: 0.40,0.81, respectively). Association between 25(OH)D and subsequent (50 years) risk of depression was non-linear (p = 0.01), with lower risk for participants with 25(OH)D between 50 and 85 nmol/l compared with those with lower or higher concentrations. This study provides support for an association of low 25(OH)D concentrations with current and subsequent risk of depression in mid-adulthood.
Publisher: MDPI AG
Date: 09-06-2023
DOI: 10.3390/NU15122703
Abstract: (1) Background: Observational studies associate vitamin D deficiency with muscle disorders, while some clinical trial data support a minor association between the vitamin and skeletal muscle performance in healthy subjects. Vitamin D receptor knockout mice studies confirm the relationship between vitamin D and skeletal muscle however, causal inference in humans is challenging due to the ethical implications of including vitamin D-deficient participants in randomized trials. This study uses genetic methods to safely explore causal underpinnings for the relationship between 25(OH)D concentrations and skeletal muscle-related traits, including grip strength and combined arm skeletal muscle mass, and extends this analysis to suspected pathophysiology in the form of probable sarcopenia and sarcopenic obesity. (2) Methods: We conducted Mendelian randomization (MR) analyses in up to 307,281 participants from the UK Biobank of whom 25,414 had probable sarcopenia and 16,520 had sarcopenic obesity. In total, 35 variants were used to instrument 25(OH)D and MR analyses conducted using multiple approaches. (3) Results: Genetic analyses provided support for a relationship between genetically predicted higher 25(OH)D and skeletal muscle traits, with linear MR analyses for grip strength showing 0.11 kg (95% CI 0.04, 0.19) greater contractile force per 10 unit higher 25(OH)D, while there was a modest association with skeletal muscle mass (0.01 kg (95% CI 0.003, 0.02) greater muscle mass). For probable sarcopenia risk, there was suggestive evidence for lower odds by higher 25(OH)D (OR 0.96 (95% CI 0.92, 1.00)) however, this did not reflect an association with sarcopenic obesity (OR 0.97 (95% CI 0.93, 1.02)), but was seen in probable sarcopenia cases who were not obese (OR 0.92 (95% CI 0.86, 0.98)). Results were similar across multiple MR approaches. (4) Conclusions: Our study supports a causal relationship between 25(OH)D and skeletal muscle health. While evidence for benefit did not extend to lower risk of sarcopenic obesity, effective vitamin D-deficiency prevention strategies may help reduce age-related muscle weakness.
Publisher: Springer Science and Business Media LLC
Date: 14-05-2018
DOI: 10.1038/S41598-018-25919-2
Abstract: Coffee’s long-term effect on cognitive function remains unclear with studies suggesting both benefits and adverse effects. We used Mendelian randomization to investigate the causal relationship between habitual coffee consumption and cognitive function in mid- to later life. This included up to 415,530 participants and 300,760 coffee drinkers from 10 meta-analysed European ancestry cohorts. In each cohort, composite cognitive scores that capture global cognition and memory were computed using available tests. A genetic score derived using CYP1A1/2 (rs2472297) and AHR (rs6968865) was chosen as a proxy for habitual coffee consumption. Null associations were observed when examining the associations of the genetic score with global and memory cognition (β = −0.0007, 95% C.I. −0.009 to 0.008, P = 0.87 β = −0.001, 95% C.I. −0.005 to 0.002, P = 0.51, respectively), with high consistency between studies (P heterogeneity 0.4 for both). Domain specific analyses using available cognitive measures in the UK Biobank also did not support effects by habitual coffee intake for reaction time, pairs matching, reasoning or prospective memory (P ≥ 0.05 for all). Despite the power to detect very small effects, our meta-analysis provided no evidence for causal long-term effects of habitual coffee consumption on global cognition or memory.
Publisher: Springer Science and Business Media LLC
Date: 08-08-2019
DOI: 10.1007/S00198-019-05118-Z
Abstract: We conducted a phenome-wide Mendelian randomization analysis (MR-PheWAS) to survey health effects associated with high normal serum calcium. We found causal evidence for conditions related to renal function, bone and joint health, and cardiovascular risk. These conditions collectively suggest that tissue calcification may be a key mechanism through which serum calcium influences health. Calcium is essential for the normal functioning of the cardiovascular system, muscles, and nerves. In this MR-PheWAS study, we sought to capture the totality of health effects associated with high normal serum calcium. We used data from up to 337,535 UK Biobank participants, and tested for associations between calcium genetic score (calcium-GS) and 925 disease outcomes, with follow-up analyses using complementary MR methods. Calcium-GS was robustly associated with serum calcium concentration (F statistics = 349). After multiple testing correction (P < 1.62E-4), we saw genetic evidence for an association between high serum calcium and urinary calculus (OR per 1 mg/dl 3.5, 95%CI 1.3-9.2), renal colic (9.1, 95%CI 2.5-33.5), and allergy/adverse effect of penicillin (2.2, 95%CI 1.5-3.3). Secondary analyses with independent replication from consortia meta-analyses suggested further effects on myocardial infarction and osteoarthrosis. We found causal evidence for effects of high normal serum calcium with conditions related to renal function, bone and joint health, and cardiovascular risk, which may collectively reflect influences on tissue calcification and immune function.
Publisher: Oxford University Press (OUP)
Date: 27-02-2013
DOI: 10.1093/HMG/DDT104
Publisher: Public Library of Science (PLoS)
Date: 22-08-2022
DOI: 10.1371/JOURNAL.PONE.0273116
Abstract: Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2 , a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 06-09-2019
Abstract: Longitudinal data find a new variant controlling BMI in infancy and reveal genetic differences between infant and adult BMI.
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1093/AJCN/NQY297
Abstract: Coffee is one of the most widely consumed stimulants worldwide and is generally considered to be safe or even beneficial for health. However, increased risk of myocardial infarction and hypertension has been suggested for in iduals who carry a functional variant at cytochrome P450 1A2 (CYP1A2), which makes them less effective at metabolizing caffeine. The aim of this study was to examine if the CYP1A2 genotype or a genetic score for caffeine metabolism (caffeine-GS) modifies the association between habitual coffee consumption and the risk of cardiovascular disease (CVD). Genetic data and information on habitual coffee intake and relevant covariates were available for 347,077 in iduals in the UK Biobank, including 8368 incident CVD cases. We used logistic regression to test for the association between coffee intake and CVD risk, and whether the association varies with CYP1A2 genotype or caffeine-GS. The association between habitual coffee intake and CVD risk was nonlinear, and, compared with participants drinking 1-2 cups/day, the risk of CVD was elevated for nondrinkers, drinkers of decaffeinated coffee, and those who reported drinking >6 cups/day (increase in odds by 11%, 7%, and 22%, respectively, P-curvature = 0.013). CYP1A2 genotype and caffeine-GS were not associated with CVD (P ≥ 0.22 for all comparisons). There was no evidence for an interaction between the CYP1A2 genotype or caffeine-GS and coffee intake with respect to risk of CVD (P ≥ 0.53). Heavy coffee consumption was associated with a modest increase in CVD risk, but this association was unaffected by genetic variants influencing caffeine metabolism.
Publisher: Springer Science and Business Media LLC
Date: 10-05-2023
Publisher: S. Karger AG
Date: 2016
DOI: 10.1159/000443136
Abstract: b i Background: /i /b Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. b i Evidence: /i /b A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describes the strength of the recommendation and the quality of supporting evidence. b i Process: /i /b Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. b i Results: /i /b This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. b i Conclusion: /i /b Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.
Publisher: Informa UK Limited
Date: 11-06-2013
DOI: 10.3109/07420528.2013.765888
Abstract: Seasonal variations in health outcomes are commonly used to hypothesize a link with nutritional vitamin D (25-hydroxyvitamin D, 25(OH)D) status. The majority of vitamin D intake is from skin exposure to sunlight and varies seasonally in countries at a distance away from the Equator. However, despite the strong seasonality of vitamin D intake, no statistical method using cyclical patterns has been proposed to deduce an association between 25(OH)D and health indicators. Our motivation was to overcome the influence of related confounders, such as obesity, between 25(OH)D and health indicators: obesity would be expected to have little or no effect on the seasonal variations in 25(OH)D and in five inflammatory/hemostatic health outcomes (fibrinogen, tissue plasminogen activator [tPA], von Willebrand factor [vWF], C-reactive protein [CRP], and D-dimer). The data analyzed was from the 1958 British birth cohort biomedical survey (n = 6195) and the biomarkers were ascertained from blood drawn over an 18-mo period. We used mediation analysis to determine whether the seasonal variations of the outcomes were mediated by 25(OH)D to infer an association. The assumptions of mediation analysis fit naturally into the study's cross-sectional setting, where day of year of blood collection is the independent variable transformed by the harmonic function, and 25(OH)D is the mediator of the seasonal variation of the outcomes. The harmonic terms were tested to establish the presence of seasonal variation in the outcomes and 25(OH)D in order to determine whether the statistical mediation test could be applied. The data were collected over an 18-mo period and assayed in multiple batches to measure the serum biomarkers. When the assay batches were modeled as fixed effects, significant correlation was found with date of when blood was drawn. Thus, variation in assay batches was accounted for as random effects terms on the intercept in linear mixed-effects models. Inferences were based on tests from mediation analysis defined by the product of regression coefficients we extended this test to allow for harmonic functions with multiple frequencies in order to statistically test the mediated effect through 25(OH)D. This was done using parametric bootstrap when the models were run in the Frequentist setting. We also replicated the analyses in the Bayesian setting to ascertain the change in litude of the seasonal variation that was due to 25(OH)D. Out of the five health outcomes, three (tPA, D-dimer, and fibrinogen) had significant seasonal associations that were partially mediated through 25(OH)D, one (vWF) had a seasonal pattern not mediated through 25(OH)D, and finally another (CRP) had no significant seasonal pattern. The association of 25(OH)D was strongest for tPA, and less so for D-dimer and fibrinogen. Our results and adaption of the mediation test show that there is broad potential in using seasonal variations of health indicators to deduce an association that may have not been affected by nonseasonal confounding.
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14132
Publisher: Frontiers Media SA
Date: 24-06-2014
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.JSBMB.2016.01.005
Abstract: Despite the high prevalence of vitamin D deficiency among older adults in the UK, studies investigating the determinants of vitamin D status in this group are lacking. We conducted a cross-sectional study in 222 older adults living in sheltered accommodation in London, UK, who were screened for participation in a clinical trial of vitamin D supplementation for the prevention of acute respiratory infection. Details of potential demographic and lifestyle determinants of vitamin D status were collected by questionnaire and blood s les were taken for analysis of serum 25-hydroxyvitamin D (25[OH]D) concentration and DNA extraction. Fifteen single nucleotide polymorphisms (SNP) in 6 genes (DBP, DHCR7, CYP2R1, CYP27B1, CYP24A1, VDR) previously reported to associate with circulating 25(OH)D concentration were typed using Taqman allelic discrimination assays. Linear regression was used to identify environmental and genetic factors independently associated with serum 25(OH)D concentration. Mean serum 25(OH)D concentration was 42.7nmol/L (SD 22.0) 144/222 (64.9%) participants had serum 25(OH)D concentrations <50nmol/L. The following factors were independently associated with lower serum 25(OH)D concentration: non-white ethnicity (-8.6nmol/L, 95% CI -14.9 to -2.3, P=0.008) lack of vitamin D supplement consumption (-17.1nmol/L, 95% CI -23.3 to -10.9, P<0.001) vs. taking a daily supplement s ling in Q1/January-March (-12.2nmol/L, 95% CI -21.5 to -2.9, P=0.01), and s ling in Q4/October-December (-10.3nmol/L, 95% CI -20.2 to -0.4, P=0.04) vs. s ling in Q3/July-September. None of the 15 SNP investigated independently associated with serum 25(OH)D concentration after correcting for multiple comparisons. In conclusion, vitamin D deficiency was highly prevalent among the older adults in this study non-White ethnicity, lack of vitamin D supplement consumption and s ling in winter and spring independently associated with lower vitamin D status.
Start Date: 06-2019
End Date: 06-2024
Amount: $404,000.00
Funder: Australian Research Council
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